Pharmaceutical combinations comprising pyrazole derivatives as protein kinase modulators

ABSTRACT

The invention provides a combination comprising an ancillary compound (e.g. one, two or more ancillary compounds) and a compound of the formula (I) having protein kinase B inhibiting activity: wherein A is a saturated hydrocarbon linker group containing from 1 to 7 carbon atoms, the linker group having a maximum chain length of 5 atoms extending between R 1  and NR 2 R 3  and a maximum chain length of 4 atoms extending between E and NR 2 R 3 , wherein one of the carbon atoms in the linker group may optionally be replaced by an oxygen or nitrogen atom; and wherein the carbon atoms of the linker group A may optionally bear one or more substituents selected from oxo, fluorine and hydroxy, provided that the hydroxy group when present is not located at a carbon atom α with respect to the NR 2 R 3  group and provided that the oxo group when present is located at a carbon atom α with respect to the NR 2 R 3  group; E is a monocyclic or bicyclic carbocyclic or heterocyclic group; R 1  is an aryl or heteroaryl group; and R 2 , R 3 , R 4  and R 5  are as defined in the claims. Also provided are patient packs, pharmaceutical kits and packs and compositions containing the combinations, methods for preparing the combinations and their use in combination therapy as anticancer agents.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a national phase filing under 35 U.S.C. §371 of PCTInternational Application PCT/GB2006/002297, filed Jun. 21, 2006, andpublished under PCT Article 21(2) in English as WO 2006/136837 on Dec.28, 2006. PCT/GB2006/002297 claimed priority from U.S. ProvisionalApplications 60/693,315, filed Jun. 23, 2005, 60/693,367, filed Jun. 23,2005, 60/693,314, filed Jun. 23, 2005, 60/693,492, filed Jun. 23, 2005and 60/693,309, filed Jun. 23, 2005. The entire contents of each of theprior applications are incorporated herein by reference.

This invention relates to combinations of pyrazole-containing aryl- andheteroaryl-alkylamine compounds that inhibit or modulate the activity ofprotein kinase B (PKB) and protein kinase A (PKA) with one or more (e.g.two or more) ancillary compounds, to the use of the combinations in thetreatment or prophylaxis of disease states or conditions mediated by PKBand PKA, and to combinations comprising novel compounds having PKB andPKA inhibitory or modulating activity. Also provided are pharmaceuticalcompositions containing the combinations.

BACKGROUND OF THE INVENTION

Protein Kinases

Protein kinases constitute a large family of structurally relatedenzymes that are responsible for the control of a wide variety of signaltransduction processes within the cell (Hardie, G. and Hanks, S. (1995)The Protein Kinase Facts Book. I and II, Academic Press, San Diego,Calif.). The kinases may be categorized into families by the substratesthey phosphorylate (e.g., protein-tyrosine, protein-serine/threonine,lipids, etc.). Sequence motifs have been identified that generallycorrespond to each of these kinase families (e.g., Hanks, S. K., Hunter,T., FASEB J., 9:576-596 (1995); Knighton, et al., Science, 253:407-414(1991); Hiles, et al., Cell, 70:419-429 (1992); Kunz, et al., Cell,73:585-596 (1993); Garcia-Bustos, et al., EMBO J., 13:2352-2361 (1994)).

Protein kinases may be characterized by their regulation mechanisms.These mechanisms include, for example, autophosphorylation,transphosphorylation by other kinases; protein-protein interactions,protein-lipid interactions, and protein-polynucleotide interactions. Anindividual protein kinase may be regulated by more than one mechanism.

Kinases regulate many different cell processes including, but notlimited to, proliferation, differentiation, apoptosis, motility,transcription, translation and other signalling processes, by addingphosphate groups to target proteins. These phosphorylation events act asmolecular on/off switches that can modulate or regulate the targetprotein biological function. Phosphorylation of target proteins occursin response to a variety of extracellular signals (hormones,neurotransmitters, growth and differentiation factors, etc.), cell cycleevents, environmental or nutritional stresses, etc. The appropriateprotein kinase functions in signalling pathways to activate orinactivate (either directly or indirectly), for example, a metabolicenzyme, regulatory protein, receptor, cytoskeletal protein, ion channelor pump, or transcription factor. Uncontrolled signalling due todefective control of protein phosphorylation has been implicated in anumber of diseases, including, for example, inflammation, cancer,allergy/asthma, diseases and conditions of the immune system, diseasesand conditions of the central nervous system, and angiogenesis.

Apoptosis or programmed cell death is an important physiological processwhich removes cells no longer required by an organism. The process isimportant in early embryonic growth and development allowing thenon-necrotic controlled breakdown, removal and recovery of cellularcomponents. The removal of cells by apoptosis is also important in themaintenance of chromosomal and genomic integrity of growing cellpopulations. There are several known checkpoints in the cell growthcycle at which DNA damage and genomic integrity are carefully monitored.The response to the detection of anomalies at such checkpoints is toarrest the growth of such cells and initiate repair processes. If thedamage or anomalies cannot be repaired then apoptosis is initiated bythe damaged cell in order to prevent the propagation of faults anderrors. Cancerous cells consistently contain numerous mutations, errorsor rearrangements in their chromosomal DNA. It is widely believed thatthis occurs in part because the majority of tumours have a defect in oneor more of the processes responsible for initiation of the apoptoticprocess. Normal control mechanisms cannot kill the cancerous cells andthe chromosomal or DNA coding errors continue to be propagated. As aconsequence restoring these pro-apoptotic signals or suppressingunregulated survival signals is an attractive means of treating cancer.

The signal transduction pathway containing the enzymesphosphatidylinositol 3-kinase (PI3K), PDK1 and PKB amongst others, haslong been known to mediate increased resistance to apoptosis or survivalresponses in many cells. There is a substantial amount of data toindicate that this pathway is an important survival pathway used by manygrowth factors to suppress apoptosis. The enzyme PI3K is activated by arange of growth and survival factors e.g. EGF, PDGF and through thegeneration of polyphosphatidylinositols, initiates the activation of thedownstream signalling events including the activity of the kinases PDK1and protein kinase B (PKB) also known as Akt. This is also true in hosttissues, e.g. vascular endothelial cells as well as neoplasias. PKB is aprotein ser/thr kinase consisting of a kinase domain together with anN-terminal PH domain and C-terminal regulatory domain. The enzyme PKBitself is phosphorylated on Thr 308 by PDK1 and on Ser 473 by an as yetunidentified kinase. Full activation requires phosphorylation at bothsites whilst association between PIP3 and the PH domain is required foranchoring of the enzyme to the cytoplasmic face of the lipid membraneproviding optimal access to substrates.

Activated PKB in turn phosphorylates a range of substrates contributingto the overall survival response. Whilst we cannot be certain that weunderstand all of the factors responsible for mediating the PKBdependent survival response, some important actions are believed to bephosphorylation and inactivation of the pro-apoptotic factor BAD andcaspase 9, phosphorylation of Forkhead transcription factors e.g. FKHRleading to their exclusion from the nucleus, and activation of theNfkappaB pathway by phosphorylation of upstream kinases in the cascade.

In addition to the anti-apoptotic and pro-survival actions of the PKBpathway, the enzyme also plays an important role in promoting cellproliferation. This action is again likely to be mediated via severalactions, some of which are thought to be phosphorylation andinactivation of the cyclin dependent kinase inhibitor ofp21^(CiP1/WAF1), and phosphorylation and activation of mTOR, a kinasecontrolling several aspects of cell growth.

The phosphatase PTEN which dephosphorylates and inactivatespolyphosphatidyl-inositols is a key tumour suppressor protein whichnormally acts to regulate the PI3K/PKB survival pathway. Thesignificance of the PI3K/PKB pathway in tumourigenesis can be judgedfrom the observation that PTEN is one of the most common targets ofmutation in human tumours, with mutations in this phosphatase havingbeen found in ˜50% or more of melanomas (Guldberg et al 1997, CancerResearch 57, 3660-3663) and advanced prostate cancers (Cairns et al 1997Cancer Research 57, 4997). These observations and others suggest that awide range of tumour types are dependent on the enhanced PKB activityfor growth and survival and would respond therapeutically to appropriateinhibitors of PKB.

There are 3 closely related isoforms of PKB called alpha, beta andgamma, which genetic studies suggest have distinct but overlappingfunctions. Evidence suggests that they can all independently play a rolein cancer. For example PKB beta has been found to be over-expressed oractivated in 10-40% of ovarian and pancreatic cancers (Bellacosa et al1995, Int. J. Cancer 64, 280-285; Cheng et al 1996, PNAS 93, 3636-3641;Yuan et 2000, Oncogene 19, 2324-2330), PKB alpha is amplified in humangastric, prostate and breast cancer (Steal 1987, PNAS 84, 5034-5037; Sunet at 2001, Am. J. Pathol. 159, 431-437) and increased PKB gammaactivity has been observed in steroid independent breast and prostatecell lines (Nakatani et at 1999, J. Biol. Chem. 274, 21528-21532).

The PKB pathway also functions in the growth and survival of normaltissues and may be regulated during normal physiology to control celland tissue function. Thus disorders associated with undesirableproliferation and survival of normal cells and tissues may also benefittherapeutically from treatment with a PKB inhibitor. Examples of suchdisorders are disorders of immune cells associated with prolongedexpansion and survival of cell population leading to a prolonged or upregulated immune response. For example, T and B lymphocyte response tocognate antigens or growth factors such as interleukin-2 activates thePI3K/PKB pathway and is responsible for maintaining the survival of theantigen specific lymphocyte clones during the immune response. Underconditions in which lymphocytes and other immune cells are responding toinappropriate self or foreign antigens, or in which other abnormalitieslead to prolonged activation, the PKB pathway contributes an importantsurvival signal preventing the normal mechanisms by which the immuneresponse is terminated via apoptosis of the activated cell population.There is a considerable amount of evidence demonstrating the expansionof lymphocyte populations responding to self antigens in autoimmuneconditions such as multiple sclerosis and arthritis. Expansion oflymphocyte populations responding inappropriately to foreign antigens isa feature of another set of conditions such as allergic responses andasthma. In summary inhibition of PKB could provide a beneficialtreatment for immune disorders.

Other examples of inappropriate expansion, growth, proliferation,hyperplasia and survival of normal cells in which PKB may play a roleinclude but are not limited to atherosclerosis, cardiac myopathy andglomerulonephritis.

In addition to the role in cell growth and survival, the PKB pathwayfunctions in the control of glucose metabolism by insulin. Availableevidence from mice deficient in the alpha and beta isoforms of PKBsuggests that this action is mediated by the beta isoform. As aconsequence, modulators of PKB activity may also find utility indiseases in which there is a dysfunction of glucose metabolism andenergy storage such as diabetes, metabolic disease and obesity.

Cyclic AMP-dependent protein kinase (PKA) is a serine/threonine proteinkinase that phosphorylates a wide range of substrates and is involved inthe regulation of many cellular processes including cell growth, celldifferentiation, ion-channel conductivity, gene transcription andsynaptic release of neurotransmitters. In its inactive form, the PKAholoenzyme is a tetramer comprising two regulatory subunits and twocatalytic subunits.

PKA acts as a link between G-protein mediated signal transduction eventsand the cellular processes that they regulate. Binding of a hormoneligand such as glucagon to a transmembrane receptor activates areceptor-coupled G-protein (GTP-binding and hydrolyzing protein). Uponactivation, the alpha subunit of the G protein dissociates and binds toand activates adenylate cyclase, which in turn converts ATP tocyclic-AMP (cAMP).

The cAMP thus produced then binds to the regulatory subunits of PKAleading to dissociation of the associated catalytic subunits. Thecatalytic subunits of PKA, which are inactive when associated with theregulatory sub-units, become active upon dissociation and take part inthe phosphorylation of other regulatory proteins.

For example, the catalytic sub-unit of PKA phosphorylates the kinasePhosphorylase Kinase which is involved in the phosphorylation ofPhosphorylase, the enzyme responsible for breaking down glycogen torelease glucose. PKA is also involved in the regulation of glucoselevels by phosphorylating and deactivating glycogen synthase. Thus,modulators of PKA activity (which modulators may increase or decreasePKA activity) may be useful in the treatment or management of diseasesin which there is a dysfunction of glucose metabolism and energy storagesuch as diabetes, metabolic disease and obesity.

PKA has also been established as an acute inhibitor of T cellactivation. Anndahl at al, have investigated the possible role of PKAtype I in HIV-induced T cell dysfunction on the basis that T cells fromHIV-infected patients have increased levels of cAMP and are moresensitive to inhibition by cAMP analogues than are normal T cells. Fromtheir studies, they concluded that increased activation of PKA type Imay contribute to progressive T cell dysfunction in HIV infection andthat PKA type I may therefore be a potential target for immunomodulatingtherapy.-Aandahl, E. M., Aukrust, P., Skålhegg, B. S., Müller, F.,Frøland, S. S., Hansson, V., Taskén, K. Protein kinase A type Iantagonist restores immune responses of T cells from HIV-infectedpatients. FASEB J. 12, 855-862 (1998).

It has also been recognised that mutations in the regulatory sub-unit ofPKA can lead to hyperactivation in endocrine tissue.

Because of the diversity and importance of PKA as a messenger in cellregulation, abnormal responses of cAMP can lead to a variety of humandiseases such as irregular cell growth and proliferation (Stratakis, C.A.; Cho-Chung, Y. S.; Protein Kinase A and human diseases. TrendsEndrocri. Metab. 2002, 13, 50-52). Over-expression of PKA has beenobserved in a variety of human cancer cells including those fromovarian, breast and colon patients. Inhibition of PKA would therefore bean approach to treatment of cancer (Li, Q.; Zhu, G-D.; Current Topics inMedicinal Chemistry, 2002, 2, 939-971).

For a review of the role of PKA in human disease, see for example,Protein Kinase A and Human Disease, Edited by Constantine A. Stratakis,Annals of the New York Academy of Sciences, Volume 968, 2002, ISBN1-57331-412-9.

Several classes of compounds have been disclosed as having PKA and PKBinhibitory activity.

For example, a class of isoquinolinyl-sulphonamido-diamines having PKBinhibitory activity is disclosed in WO 01/91754 (Yissum).

WOO/07996 (Chiron) discloses substituted pyrazoles having estrogenreceptor agonist activity. The compounds are described as being usefulin treating or preventing inter alia estrogen-receptor mediated breastcancer. PKB inhibitory activity is not disclosed.

WO 00/31063 (Searle) discloses substituted pyrazole compounds as p38kinase inhibitors.

WO 01/32653 (Cephalon) discloses a class of pyrazolone kinaseinhibitors. WO 03/059884 (X-Ceptor Therapeutics) discloses N-substitutedpyridine compounds as modulators of nuclear receptors.

WO 03/068230 (Pharmacia) discloses substituted pyridones as p38 MAPkinase modulators.

WO 00/66562 (Dr Reddy's Research Foundation) discloses a class of1-phenyl-substituted pyrazoles for use as anti-inflammatory agents. The1-phenyl group is substituted by a sulphur-containing substituent as asulphonamide or sulphonyl group.

Ancillary Compounds

A wide variety of ancillary compounds find application in thecombinations of the invention, as described in detail below.

It is an object of the invention to provide therapeutic combinationscomprising an ancillary compound (e.g. one, two or more ancillarycompounds) and a compound that has protein kinase B (PKB) and/or proteinkinase A (PKA) inhibiting or modulating activity and which have anadvantageous efficacious effect in comparison with the respectiveeffects shown by the individual components of the combination.

SUMMARY OF THE INVENTION

The invention provides combinations of an ancillary compound (e.g. one,two or more ancillary compounds) with compounds that have protein kinaseB (PKB) and/or protein kinase A (PKA) inhibiting or modulating activity,and which it is envisaged will be useful in preventing or treatingdisease states or conditions mediated by PKB and/or PKA.

In a first aspect, the invention provides a combination of an ancillarycompound (e.g. one, two or more ancillary compounds) and a compound ofthe formula (I):

or a salt, solvate, tautomer or N-oxide thereof;

wherein A is a saturated hydrocarbon linker group containing from 1 to 7carbon atoms, the linker group having a maximum chain length of 5 atomsextending between R¹ and NR²R³ and a maximum chain length of 4 atomsextending between E and NR²R³, wherein one of the carbon atoms in thelinker group may optionally be replaced by an oxygen or nitrogen atom;and wherein the carbon atoms of the linker group A may optionally bearone or more substituents selected from oxo, fluorine and hydroxy,provided that the hydroxy group when present is not located at a carbonatom a with respect to the NR²R³ group and provided that the oxo groupwhen present is located at a carbon atom a with respect to the NR²R³group;

-   -   E is a monocyclic or bicyclic carbocyclic or heterocyclic group;    -   R¹ is an aryl or heteroaryl group;    -   R² and R³ are independently selected from hydrogen, C₁₋₄        hydrocarbyl and C₁₋₄ acyl wherein the hydrocarbyl and acyl        moieties are optionally substituted by one or more substituents        selected from fluorine, hydroxy, amino, methylamino,        dimethylamino and methoxy;        -   or R² and R³ together with the nitrogen atom to which they            are attached form a cyclic group selected from an imidazole            group and a saturated monocyclic heterocyclic group having            4-7 ring members and optionally containing a second            heteroatom ring member selected from O and N;        -   or one of R² and R³ together with the nitrogen atom to which            they are attached and one or more atoms from the linker            group A form a saturated monocyclic heterocyclic group            having 4-7 ring members and optionally containing a second            heteroatom ring member selected from O and N;        -   or NR²R³ and the carbon atom of linker group A to which it            is attached together form a cyano group;    -   R⁴ is selected from hydrogen, halogen, C₁₋₅ saturated        hydrocarbyl, C₁₋₅ saturated hydrocarbyloxy, cyano, and CF₃; and    -   R⁵ is selected from selected from hydrogen, halogen, C₁₋₅        saturated hydrocarbyl, C₁₋₅ saturated hydrocarbyloxy, cyano,        CONH₂, CONHR⁹, CF₃, NH₂, NHCOR⁹ or NHCONHR⁹;        -   R⁹ is a group R^(9a) or (CH₂)R^(9a), wherein R^(9a) is a            monocyclic or bicyclic group which may be carbocyclic or            heterocyclic;    -   the carbocyclic group or heterocyclic group R^(9a) being        optionally substituted by one or more substituents selected from        halogen, hydroxy, trifluoromethyl, cyano, nitro, carboxy, amino,        mono- or di-C₁₋₄ hydrocarbylamino; a group R^(a)—R^(b) wherein        R^(a) is a bond, O, CO, X¹C(X²), C(X²)X¹, X¹C(X²)X¹, S, SO, SO₂,        NR^(c), SO₂NR^(c) or NR^(c)SO₂; and R^(b) is selected from        hydrogen, heterocyclic groups having from 3 to 12 ring members,        and a C₁₋₈ hydrocarbyl group optionally substituted by one or        more substituents selected from hydroxy, oxo, halogen, cyano,        nitro, carboxy, amino, mono- or di-C₁₋₄ hydrocarbylamino,        carbocyclic and heterocyclic groups having from 3 to 12 ring        members and wherein one or more carbon atoms of the C₁₋₈        hydrocarbyl group may optionally be replaced by O, S, SO, SO₂,        NR^(c), X¹C(X²), C(X²)X¹ or X¹C(X²)X¹;    -   R^(c) is selected from hydrogen and C₁₋₄ hydrocarbyl; and    -   X¹ is O, S or NR^(c) and X² is ═O, ═S or ═NR^(c).

The combinations of the invention may comprise (or consist essentiallyof) an ancillary compound (e.g. one, two or more ancillary compounds)and a compound of the formula (I) as defined herein. Thus, in oneembodiment, the combinations of the invention comprise (or consistessentially of) one ancillary compound and a compound of the formula (I)as defined herein. In another embodiment, the combinations of theinvention comprise (or consist essentially of) two or more ancillarycompounds and a compound of the formula (I) as defined herein.

The invention also provides a combination of an ancillary compound (e.g.one, two or more ancillary compounds) and a compound of the formula(Ia):

or a salt, solvate, tautomer or N-oxide thereof;

wherein A is a saturated hydrocarbon linker group containing from 1 to 7carbon atoms, the linker group having a maximum chain length of 5 atomsextending between R¹ and NR²R³ and a maximum chain length of 4 atomsextending between E and NR²R³, wherein one of the carbon atoms in thelinker group may optionally be replaced by an oxygen or nitrogen atom;and wherein the carbon atoms of the linker group A may optionally bearone or more substituents selected from oxo, fluorine and hydroxy,provided that the hydroxy group when present is not located at a carbonatom a with respect to the NR²R³ group and provided that the oxo groupwhen present is located at a carbon atom a with respect to the NR²R³group;

-   -   E is a monocyclic or bicyclic carbocyclic or heterocyclic group;    -   R¹ is an aryl or heteroaryl group;    -   R² and R³ are independently selected from hydrogen, C₁₋₄        hydrocarbyl and C₁₋₄ acyl;    -   or R² and R³ together with the nitrogen atom to which they are        attached form a saturated monocyclic heterocyclic group having        4-7 ring members and optionally containing a second heteroatom        ring member selected from O and N;    -   or one of R² and R³ together with the nitrogen atom to which        they are attached and one or more atoms from the linker group A        form a saturated monocyclic heterocyclic group having 4-7 ring        members and optionally containing a second heteroatom ring        member selected from O and N;    -   or NR²R³ and the carbon atom of linker group A to which it is        attached together form a cyano group;    -   R⁴ is selected from hydrogen, halogen, C₁₋₅ saturated        hydrocarbyl, cyano and CF₃; and    -   R⁵ is selected from hydrogen, halogen, C₁₋₅ saturated        hydrocarbyl, cyano, CONH₂, CONHR⁹, CF₃, NH₂, NHCOR⁹ or NHCONHR⁹;    -   R⁹ is phenyl or benzyl each optionally substituted by one or        more substituents selected from halogen, hydroxy,        trifluoromethyl, cyano, nitro, carboxy, amino, mono- or di-C₁₋₄        hydrocarbylamino; a group R^(a)—R^(b) wherein R^(a) is a bond,        O, CO, X¹C(X²), C(X²)X¹, X¹C(X²)X¹, S, SO, SO₂, NR^(c),        SO₂NR^(c) or NR^(c)SO₂; and R^(b) is selected from hydrogen,        heterocyclic groups having from 3 to 12 ring members, and a C₁₋₈        hydrocarbyl group optionally substituted by one or more        substituents selected from hydroxy, oxo, halogen, cyano, nitro,        carboxy, amino, mono- or di-C₁₋₄ hydrocarbylamino, carbocyclic        and heterocyclic groups having from 3 to 12 ring members and        wherein one or more carbon atoms of the C₁₋₈ hydrocarbyl group        may optionally be replaced by O, S, SO, SO₂, NR^(c), X¹C(X²),        C(X²)X¹ or X¹C(X²)X¹;    -   R^(c) is selected from hydrogen and C₁₋₄ hydrocarbyl; and    -   X¹ is O, S or NR^(c) and X² is ═O, ═S or ═NR^(c).

Also provided are combinations of an ancillary compound (e.g. one, twoor more ancillary compounds) and compounds of the general formula (Ib):

or salts, solvates, tautomers or N-oxides thereof;

wherein A is a saturated hydrocarbon linker group containing from 1 to 7carbon atoms, the linker group having a maximum chain length of 5 atomsextending between R¹ and NR²R³ and a maximum chain length of 4 atomsextending between E and NR²R³, wherein one of the carbon atoms in thelinker group may optionally be replaced by an oxygen or nitrogen atom;and wherein the carbon atoms of the linker group A may optionally bearone or more substituents selected from fluorine and hydroxy, providedthat the hydroxy group is not located at a carbon atom a with respect tothe NR²R³ group;

-   -   E is a monocyclic or bicyclic carbocyclic or heterocyclic group;    -   R¹ is an aryl or heteroaryl group;    -   R² and R³ are independently selected from hydrogen, C₁₋₄        hydrocarbyl and C₁₋₄ acyl;    -   or R² and R³ together with the nitrogen atom to which they are        attached form a saturated monocyclic heterocyclic group having        4-7 ring members and optionally containing a second heteroatom        ring member selected from O and N;    -   or one of R² and R³ together with the nitrogen atom to which        they are attached and one or more atoms from the linker group A        form a saturated monocyclic heterocyclic group having 4-7 ring        members and optionally containing a second heteroatom ring        member selected from O and N;    -   or NR²R³ and the carbon atom of linker group A to which it is        attached together form a cyano group;    -   R⁴ is selected from hydrogen, halogen, C₁₋₅ saturated        hydrocarbyl, cyano, and CF₃; and    -   R⁵ is selected from selected from hydrogen, halogen, C₁₋₅        saturated hydrocarbyl, cyano, CONH₂, CF₃, NH₂, NHCOR⁹ or        NHCONHR⁹;    -   R⁹ is phenyl or benzyl each optionally substituted by one or        substituents selected from halogen, hydroxy, trifluoromethyl,        cyano, nitro, carboxy, amino, mono- or di-C₁₄ hydrocarbylamino;        a group R^(a)—R^(b) wherein R^(a) is a bond, O, CO, X¹C(X²)X¹,        X¹C(X²)X¹, S, SO, SO₂, NR^(c), SO₂NR^(c) or NR^(c)SO₂; and R^(b)        is selected from hydrogen, heterocyclic groups having from 3 to        12 ring members, and a C₁₋₅ hydrocarbyl group optionally        substituted by one or more substituents selected from hydroxy,        oxo, halogen, cyano, nitro, carboxy, amino, mono- or di-C₁₋₄        hydrocarbylamino, carbocyclic and heterocyclic groups having        from 3 to 12 ring members and wherein one or more carbon atoms        of the C₁₋₈ hydrocarbyl group may optionally be replaced by O,        S, SO, SO₂, NR^(c), X¹C(X²), C(X²)X¹ or X¹C(X²)X¹;    -   R^(c) is selected from hydrogen and C₁₋₄ hydrocarbyl; and    -   X¹ is O, S or NR^(c) and X², is ═O, ═S or ═NR^(c).

The invention further provides:

-   -   A combination of an ancillary compound (e.g. one, two or more        ancillary compounds) and a compound per se of the formula (II),        (III), (IV), (V) or any other sub-group or embodiment of the        formula (I) as defined herein.    -   A combination of an ancillary compound (e.g. one, two or more        ancillary compounds) and a compound of the formula (I), (Ia),        (Ib), (II), (III), (IV), (V) or any sub-group thereof as defined        herein for use in the prophylaxis or treatment of a disease        state or condition mediated by protein kinase B.    -   The use of a combination of an ancillary compound (e.g. one, two        or more ancillary compounds) and a compound of formula (I),        (Ia), (Ib), (II), (III), (IV), (V) or any sub-group thereof as        defined herein for the manufacture of a medicament for the        prophylaxis or treatment of a disease state or condition        mediated by protein kinase B.    -   A method for the prophylaxis or treatment of a disease state or        condition mediated by protein kinase B, which method comprises        administering to a subject in need thereof a combination of an        ancillary compound (e.g. one, two or more ancillary compounds)        and a compound of the formula (I), (Ia), (Ib), (II), (III),        (IV), (V) or any sub-group thereof as defined herein.    -   A method for treating a disease or condition comprising or        arising from abnormal cell growth or abnormally arrested cell        death in a mammal, the method comprising administering to the        mammal a combination of an ancillary compound (e.g. one, two or        more ancillary compounds) and a compound of the formula (I),        (Ia), (Ib), (II), (III), (IV), (V) or any sub-group thereof as        defined herein in an amount effective to inhibit protein kinase        B activity.    -   A method of inhibiting protein kinase B, which method comprises        contacting the kinase with a combination of an ancillary        compound (e.g. one, two or more ancillary compounds) and a        kinase-inhibiting compound of the formula (I), (Ia), (Ib), (II),        (III), (IV), (V) or any sub-group thereof as defined herein.    -   A method of modulating a cellular process (for example cell        division) by inhibiting the activity of a protein kinase B using        a combination of an ancillary compound (e.g. one, two or more        ancillary compounds) and a compound of the formula (I), (Ia),        (Ib), (II), (III), (IV), (V) or any sub-group thereof as defined        herein.    -   A combination of an ancillary compound (e.g. one, two or more        ancillary compounds) and a compound of the formula (I), (Ia),        (Ib), (II), (III), (IV), (V) or any sub-group or embodiment        thereof as defined herein for use in the prophylaxis or        treatment of a disease state or condition mediated by protein        kinase A.    -   The use of a combination of an ancillary compound (e.g. one, two        or more ancillary compounds) and a compound of formula (I),        (Ia), (Ib), (II), (III), (IV), (V) or any sub-group or        embodiment thereof as defined herein for the manufacture of a        medicament for the prophylaxis or treatment of a disease state        or condition mediated by protein kinase A.    -   A method for the prophylaxis or treatment of a disease state or        condition mediated by protein kinase A, which method comprises        administering to a subject in need thereof a combination of an        ancillary compound (e.g. one, two or more ancillary compounds)        and a compound of the formula (I), (Ia), (Ib), (II), (III),        (IV), (V) or any sub-group or embodiment thereof as defined        herein.    -   A method for treating a disease or condition comprising or        arising from abnormal cell growth or abnormally arrested cell        death in a mammal, the method comprising administering to the        mammal a combination of an ancillary compound (e.g. one, two or        more ancillary compounds) and a compound of the formula (I),        (Ia), (Ib), (II), (III), (IV), (V) or any sub-group or        embodiment thereof as defined herein in an amount effective to        inhibit protein kinase A activity.    -   A method of inhibiting protein kinase A, which method comprises        contacting the kinase with a combination of an ancillary        compound (e.g. one, two or more ancillary compounds) and a        kinase-inhibiting compound of the formula (I), (Ia), (Ib), (II),        (III), (IV), (V) or any sub-group or embodiment thereof as        defined herein.    -   A method of modulating a cellular process (for example cell        division) by inhibiting the activity of a protein kinase A using        a combination of an ancillary compound (e.g. one, two or more        ancillary compounds) and a compound of the formula (I), (Ia),        (Ib), (II), (III), (IV), (V) or any sub-group or embodiment        thereof as defined herein.    -   The use of a combination of an ancillary compound (e.g. one, two        or more ancillary compounds) and a compound of the formula (I),        (Ia), (Ib), (II), (III), (IV), (V) or any sub-group thereof as        defined herein for the manufacture of a medicament for the        prophylaxis or treatment of a disease state or condition arising        from abnormal cell growth or abnormally arrested cell death.    -   A method for treating a disease or condition comprising or        arising from abnormal cell growth in a mammal, which method        comprises administering to the mammal a combination of an        ancillary compound (e.g. one, two or more ancillary compounds)        and a compound of the formula (I), (Ia), (Ib), (II), (III),        (IV), (V) or any sub-group thereof as defined herein in an        amount effective in inhibiting abnormal cell growth or        abnormally arrested cell death.    -   A method for alleviating or reducing the incidence of a disease        or condition comprising or arising from abnormal cell growth or        abnormally arrested cell death in a mammal, which method        comprises administering to the mammal a combination of an        ancillary compound (e.g. one, two or more ancillary compounds)        and a compound of the formula (I), (Ia), (Ib), (II), (III),        (IV), (V) or any sub-group thereof as defined herein in an        amount effective in inhibiting abnormal cell growth.    -   A pharmaceutical composition comprising a combination of an        ancillary compound (e.g. one, two or more ancillary compounds)        and a novel compound of the formula (I), (Ia), (Ib), (II),        (III), (IV), (V) or any sub-group thereof as defined herein and        a pharmaceutically acceptable carrier.    -   A combination of an ancillary compound (e.g. one, two or more        ancillary compounds) and a compound of the formula (I), (Ia),        (Ib), (II), (III), (IV), (V) or any sub-group thereof as defined        herein for use in medicine.    -   The use of a combination of an ancillary compound (e.g. one, two        or more ancillary compounds) and a compound of the formula (I),        (Ia), (Ib), (II), (III), (IV), (V) or any sub-group thereof as        defined herein for the manufacture of a medicament for the        prophylaxis or treatment of any one of the disease states or        conditions disclosed herein.    -   A method for the treatment or prophylaxis of any one of the        disease states or conditions disclosed herein, which method        comprises administering to a patient (e.g. a patient in need        thereof) a combination of an ancillary compound (e.g. one, two        or more ancillary compounds) and a compound (e.g. a        therapeutically effective amount) of the formula (I), (Ia),        (Ib), (II), (III), (IV), (V) or any sub-group thereof as defined        herein.    -   A method for alleviating or reducing the incidence of a disease        state or condition disclosed herein, which method comprises        administering to a patient (e.g. a patient in need thereof) a        combination of an ancillary compound (e.g. one, two or more        ancillary compounds) and a compound (e.g. a therapeutically        effective amount) of the formula (I), (Ia), (Ib), (II), (III),        (IV), (V) or any sub-group thereof as defined herein.    -   A method for the diagnosis and treatment of a disease state or        condition mediated by protein kinase B, which method        comprises (i) screening a patient to determine whether a disease        or condition from which the patient is or may be suffering is        one which would be susceptible to treatment with a compound        having activity against protein kinase B; and (ii) where it is        indicated that the disease or condition from which the patient        is thus susceptible, thereafter administering to the patient a        combination of an ancillary compound (e.g. one, two or more        ancillary compounds) and a compound of the formula (I), (Ia),        (Ib), (II), (III), (IV), (V) or any sub-group thereof as defined        herein.    -   The use of a combination of an ancillary compound (e.g. one, two        or more ancillary compounds) and a compound of the formula (I),        (Ia), (Ib), (II), (III), (IV), (V) or any sub-group thereof as        defined herein for the manufacture of a medicament for the        treatment or prophylaxis of a disease state or condition in a        patient who has been screened and has been determined as        suffering from, or being at risk of suffering from, a disease or        condition which would be susceptible to treatment with a        compound having activity against protein kinase B.    -   A method for the diagnosis and treatment of a disease state or        condition mediated by protein kinase A, which method        comprises (i) screening a patient to determine whether a disease        or condition from which the patient is or may be suffering is        one which would be susceptible to treatment with a compound        having activity against protein kinase A; and (ii) where it is        indicated that the disease or condition from which the patient        is thus susceptible, thereafter administering to the patient a        combination of an ancillary compound (e.g. one, two or more        ancillary compounds) and a compound of the formula (I), (Ia),        (Ib), (II), (III), (IV), (V) or any sub-group or embodiment        thereof as defined herein.    -   The use of a combination of an ancillary compound (e.g. one, two        or more ancillary compounds) and a compound of the formula (I),        (Ia), (Ib), (II), (III), (IV), (V) or any sub-group or        embodiment thereof as defined herein for the manufacture of a        medicament for the treatment or prophylaxis of a disease state        or condition in a patient who has been screened and has been        determined as suffering from, or being at risk of suffering        from, a disease or condition which would be susceptible to        treatment with a compound having activity against protein kinase        A.

The invention also provides the further combinations, uses, methods,compounds and processes as set out in the claims below, including:

-   -   A combination comprising (or consisting essentially of) an        ancillary compound and a compound of the formula (I) as defined        herein wherein the ancillary compound and compound of        formula (I) are physically associated.    -   A combination comprising (or consisting essentially of) an        ancillary compound and a compound of the formula (I) as defined        herein wherein the ancillary compound and compound of        formula (I) are non-physically associated.    -   A combination comprising (or consisting essentially of) an        ancillary compound and a compound of the formula (I) as defined        herein in the form of a pharmaceutical pack, kit or patient        pack.    -   A compound of the formula (I) as defined herein for use in the        prophylaxis or treatment of a disease state or condition        mediated by protein kinase B in a subject undergoing treatment        with an ancillary compound.    -   The use of a compound of the formula (I) as defined herein for        the manufacture of a medicament for the prophylaxis or treatment        of a disease state or condition mediated by protein kinase B in        a subject undergoing treatment with an ancillary compound.    -   A method for the prophylaxis or treatment of a disease state or        condition mediated by protein kinase B, which method comprises        administering to a subject in need thereof a compound of the        formula (I) as defined herein, wherein the subject is undergoing        treatment with an ancillary compound.    -   A method for treating a disease or condition comprising or        arising from abnormal cell growth in a mammalian subject, which        subject is undergoing treatment with an ancillary compound, the        method comprising administering a compound of the formula (I) as        defined herein in an amount effective to inhibit abnormal cell        growth.    -   A method for treating a disease or condition comprising or        arising from abnormal cell growth in a mammalian subject, which        subject is undergoing treatment with an ancillary compound, the        method comprising administering to the mammal a compound of the        formula (I) as defined herein in an amount effective to inhibit        PKB activity.    -   A method for treating an immune disorder in a mammalian subject,        which subject is undergoing treatment with an ancillary        compound, the method comprising administering to the mammal a        compound of the formula (I) as defined herein in an amount        effective to inhibit PKB activity.    -   A compound of the formula (I) defined herein for use in the        prophylaxis or treatment of a disease state or condition        mediated by protein kinase A in a subject undergoing treatment        with an ancillary compound.    -   The use of a compound of the formula (I) as defined herein for        the manufacture of a medicament for the prophylaxis or treatment        of a disease state or condition mediated by protein kinase A in        a subject undergoing treatment with an ancillary compound.    -   The use of a compound of the formula (I) as defined herein for        the manufacture of a medicament for the prophylaxis or treatment        of a disease state or condition arising from abnormal cell        growth in a subject undergoing treatment with an ancillary        compound.    -   The use of a compound of the formula (I) as defined herein for        the manufacture of a medicament for the prophylaxis or treatment        of a disease in which there is a disorder of proliferation,        apoptosis or differentiation in a subject undergoing treatment        with an ancillary compound.    -   A method for the prophylaxis or treatment of a disease state or        condition mediated by protein kinase A in a subject undergoing        treatment with an ancillary compound, which method comprises        administering to the subject a compound of the formula (I) as        defined herein.    -   A method for treating a disease or condition comprising or        arising from abnormal cell growth in a mammalian subject        undergoing treatment with an ancillary compound, the method        comprising administering to the subject a compound of the        formula (I) as defined herein in an amount effective to inhibit        PKA.    -   A method of inhibiting a protein kinase A in a subject        undergoing treatment with an ancillary compound, which method        comprises contacting the kinase with a kinase-inhibiting        compound of the formula (I) as defined herein.    -   A method of modulating a cellular process in a subject        undergoing treatment with an ancillary compound by inhibiting        the activity of a protein kinase A using a compound of the        formula (I) as defined herein.    -   A method for treating an immune disorder in a mammalian subject        undergoing treatment with an ancillary compound, the method        comprising administering to the mammal a compound of the        formula (I) as defined herein in an amount effective to inhibit        PKA activity.    -   A method of inducing apoptosis in a cancer cell in a subject        undergoing treatment with an ancillary compound, which method        comprises contacting the cancer cell with a compound of the        formula (I) as defined herein.    -   An ancillary compound (e.g. an ancillary compound selected from        any of the ancillary compounds disclosed herein) for use in        combination therapy with a compound of the formula (I) as        defined herein.    -   A compound of the formula (I) as defined herein for use in        combination therapy with an ancillary compound (e.g. an        ancillary compound selected from any of the ancillary compounds        disclosed herein).    -   Use of an ancillary compound (e.g. an ancillary compound        selected from any of the ancillary compounds disclosed herein)        for the manufacture of a medicament for use in the treatment or        prophylaxis of a patient undergoing treatment with a compound of        the formula (I) as defined herein.    -   Use of a compound of the formula (I) as defined herein for the        manufacture of a medicament for use in the treatment or        prophylaxis of a patient undergoing treatment with an ancillary        compound (e.g. an ancillary compound selected from any of the        ancillary compounds disclosed herein).    -   A method for the treatment of a cancer in a warm-blooded animal        such as a human, which comprises administering to said animal an        effective amount of an ancillary compound (e.g. an ancillary        compound selected from any of the ancillary compounds disclosed        herein) sequentially e.g. before or after, or simultaneously        with an effective amount of a compound of the formula (I) as        defined herein.    -   A method of combination cancer therapy in a mammal comprising        administering a therapeutically effective amount of an ancillary        compound (e.g. an ancillary compound selected from any of the        ancillary compounds disclosed herein) and a therapeutically        effective amount of a compound of the formula (I) as defined        herein.    -   A compound of the formula (I) as defined herein for use in        combination therapy with an ancillary compound (e.g. an        ancillary compound selected from any of the ancillary compounds        disclosed herein) to alleviate or reduce the incidence of a        disease or condition comprising or arising from abnormal cell        growth in a mammal.    -   A compound of the formula (I) as defined herein for use in        combination therapy with an ancillary compound (e.g. an        ancillary compound selected from any of the ancillary compounds        disclosed herein) to inhibit tumour growth in a mammal.    -   A compound of the formula (I) as defined herein for use in        combination therapy with an ancillary compound (e.g. an        ancillary compound selected from any of the ancillary compounds        disclosed herein) to prevent, treat or manage cancer in a        patient in need thereof.    -   A compound of the formula (I) as defined herein for use in        enhancing or potentiating the response rate in a patient        suffering from a cancer where the patient is being treated with        an ancillary compound (e.g. an ancillary compound selected from        any of the ancillary compounds disclosed herein).    -   A method of enhancing or potentiating the response rate in a        patient suffering from a cancer where the patient is being        treated with an ancillary compound (e.g. an ancillary compound        selected from any of the ancillary compounds disclosed herein),        which method comprises administering to the patient, in        combination with the ancillary compound, a compound of the        formula (I) as defined herein.    -   A process for the production of a combination comprising (or        consisting essentially of) an ancillary compound and a compound        of the formula (I) as defined herein, which process comprises        combining a compound of formula I with an ancillary compound.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1. depicts results from an IC₅₀ shift assay run using4-(4-Chloro-phenyl)-4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidine ascompound I and gefitinib (Iressa) as compound II.

GENERAL PREFERENCES AND DEFINITIONS

As used herein, the term “modulation”, as applied to PKB and/or PKAactivity, is intended to define a change in the level of biologicalactivity of the PKB and/or PKA enzyme(s). Thus, modulation encompassesphysiological changes which effect an increase or decrease in PKA and/orPKB activity. In the latter case, the modulation may be described as“inhibition”. The modulation may arise directly or indirectly, and maybe mediated by any mechanism and at any physiological level, includingfor example at the level of gene expression (including for exampletranscription, translation and/or post-translational modification), atthe level of expression of genes encoding regulatory elements which actdirectly or indirectly on the levels of PKA and/or PKB activity, or atthe level of enzyme (e.g. PKB and/or PKA) activity (for example byallosteric mechanisms, competitive inhibition, active-site inactivation,perturbation of feedback inhibitory pathways etc.). Thus, modulation mayimply elevated/suppressed expression or over- or under-expression of thePKA and/or PKB, including gene amplification (i.e. multiple gene copies)and/or increased or decreased expression by a transcriptional effect, aswell as hyper- (or hypo-)activity and (de)activation of the PKA and/orPKB (including (de)activation) by mutation(s). The terms “modulated” and“modulate” are to be interpreted accordingly.

As used herein, the term “mediated”, as used e.g. in conjunction withthe PKB and/or PKAs as described herein (and applied for example tovarious physiological processes, diseases, states, conditions,therapies, treatments or interventions) is intended to operatelimitatively so that the various processes, diseases, states,conditions, treatments and interventions to which the term is appliedare those in which PKA and/or PKB plays a biological role. In caseswhere the term is applied to a disease, state or condition, the roleplayed by PKA and/or PKB may be direct or indirect and may be necessaryand/or sufficient for the manifestation of the symptoms of the disease,state or condition (or its aetiology or progression). Thus, PKA and/orPKB activity (and in particular aberrant levels of PKA and/or PKBactivity, e.g. PKA and/or PKB over-expression) need not necessarily bethe proximal cause of the disease, state or condition: rather, it iscontemplated that PKA- and/or PKB-mediated diseases, states orconditions include those having multifactorial aetiologies and complexprogressions in which PKA and/or PKB is only partially involved. Incases where the term is applied to treatment, prophylaxis orintervention (e.g. in the “PKB-mediated treatments” and “PKB-mediatedprophylaxis” of the invention), the role played by PKA and/or PKB may bedirect or indirect and may be necessary and/or sufficient for theoperation of the treatment, prophylaxis or outcome of the intervention.

The term “intervention” is a term of art used herein to define anyagency which effects a physiological change at any level. Thus, theintervention may comprises the induction or repression of anyphysiological process, event, biochemical pathway orcellular/biochemical event. The interventions of the invention typicallyeffect (or contribute to) the therapy, treatment or prophylaxis of adisease or condition.

The following general preferences and definitions shall apply to each ofthe moieties A, E and R¹ to R⁵ and R⁹ and any sub-definition, sub-groupor embodiment thereof, unless the context indicates otherwise.

Any references to Formula (I) herein shall be taken also to refer toformulae (Ia), (Ib), (II), (III), (IV), (V) and any other sub-group ofcompounds within formula (I) unless the context requires otherwise.

References to “carbocyclic” and “heterocyclic” groups as used hereinshall, unless the context indicates otherwise, include both aromatic andnon-aromatic ring systems. In general, such groups may be monocyclic orbicyclic and may contain, for example, 3 to 12 ring members, moreusually 5 to 10 ring members. Examples of monocyclic groups are groupscontaining 3, 4, 5, 6, 7, and 8 ring members, more usually 3 to 7, andpreferably 5 or 6 ring members. Examples of bicyclic groups are thosecontaining 8, 9, 10, 11 and 12 ring members, and more usually 9 or 10ring members.

The carbocyclic or heterocyclic groups can be aryl or heteroaryl groupshaving from 5 to 12 ring members, more usually from 5 to 10 ringmembers. The term “aryl” as used herein refers to a carbocyclic grouphaving aromatic character and the term “heteroaryl” is used herein todenote a heterocyclic group having aromatic character. The terms “aryl”and “heteroaryl” embrace polycyclic (e.g. bicyclic) ring systems whereinone or more rings are non-aromatic, provided that at least one ring isaromatic. In such polycyclic systems, the group may be attached by thearomatic ring, or by a non-aromatic ring. The aryl or heteroaryl groupscan be monocyclic or bicyclic groups and can be unsubstituted orsubstituted with one or more substituents, for example one or moregroups R¹⁰ as defined herein.

The term non-aromatic group embraces unsaturated ring systems withoutaromatic character, partially saturated and fully saturated carbocyclicand heterocyclic ring systems. The terms “unsaturated” and “partiallysaturated” refer to rings wherein the ring structure(s) contains atomssharing more than one valence bond i.e. the ring contains at least onemultiple bond e.g. a C═C, C≡C or N═C bond. The term “fully saturated”refers to rings where there are no multiple bonds between ring atoms.Saturated carbocyclic groups include cycloalkyl groups as defined below.Partially saturated carbocyclic groups include cycloalkenyl groups asdefined below, for example cyclopentenyl, cycloheptenyl andcyclooctenyl.

Examples of heteroaryl groups are monocyclic and bicyclic groupscontaining from five to twelve ring members, and more usually from fiveto ten ring members. The heteroaryl group can be, for example, a fivemembered or six membered monocyclic ring or a bicyclic structure formedfrom fused five and six membered rings or two fused six membered rings.Each ring may contain up to about four heteroatoms typically selectedfrom nitrogen, sulphur and oxygen. Typically the heteroaryl ring willcontain up to 3 heteroatoms, more usually up to 2, for example a singleheteroatom. In one embodiment, the heteroaryl ring contains at least onering nitrogen atom. The nitrogen atoms in the heteroaryl rings can bebasic, as in the case of an imidazole or pyridine, or essentiallynon-basic as in the case of an indole or pyrrole nitrogen. In generalthe number of basic nitrogen atoms present in the heteroaryl group,including any amino group substituents of the ring, will be less thanfive.

Examples of five membered heteroaryl groups include but are not limitedto pyrrole, furan, thiophene, imidazole, furazan, oxazole, oxadiazole,oxatriazole, isoxazole, thiazole, isothiazole, pyrazole, triazole andtetrazole groups.

Examples of six membered heteroaryl groups include but are not limitedto pyridine, pyrazine, pyridazine, pyrimidine and triazine.

A bicyclic heteroaryl group may be, for example, a group selected from:

-   -   a) a benzene ring fused to a 5- or 6-membered ring containing 1,        2 or 3 ring heteroatoms;    -   b) a pyridine ring fused to a 5- or 6-membered ring containing        1, 2 or 3 ring heteroatoms;    -   c) a pyrimidine ring fused to a 5- or 6-membered ring containing        1 or 2 ring heteroatoms;    -   d) a pyrrole ring fused to a a 5- or 6-membered ring containing        1, 2 or 3 ring heteroatoms;    -   e) a pyrazole ring fused to a a 5- or 6-membered ring containing        1 or 2 ring heteroatoms;    -   f) an imidazole ring fused to a 5- or 6-membered ring containing        1 or 2 ring heteroatoms;    -   g) an oxazole ring fused to a 5- or 6-membered ring containing 1        or 2 ring heteroatoms;    -   h) an isoxazole ring fused to a 5- or 6-membered ring containing        1 or 2 ring heteroatoms;    -   i) a thiazole ring fused to a 5- or 6-membered ring containing 1        or 2 ring heteroatoms;    -   j) an isothiazole ring fused to a 5- or 6-membered ring        containing 1 or 2 ring heteroatoms;    -   k) a thiophene ring fused to a 5- or 6-membered ring containing        1, 2 or 3 ring heteroatoms;    -   l) a furan ring fused to a 5- or 6-membered ring containing 1, 2        or 3 ring heteroatoms;    -   m) an oxazole ring fused to a 5- or 6-membered ring containing 1        or 2 ring heteroatoms;    -   n) an isoxazole ring fused to a 5- or 6-membered ring containing        1 or 2 ring heteroatoms;    -   o) a cyclohexyl ring fused to a 5- or 6-membered ring containing        1, 2 or 3 ring heteroatoms; and    -   p) a cyclopentyl ring fused to a 5- or 6-membered ring        containing 1, 2 or 3 ring heteroatoms.

Examples of bicyclic heteroaryl groups containing a six membered ringfused to a five membered ring include but are not limited to benzfuran,benzthiophene, benzimidazole, benzoxazole, benzisoxazole, benzthiazole,benzisothiazole, isobenzofuran, indole, isoindole, indolizine, indoline,isoindoline, purine (e.g., adenine, guanine), indazole, benzodioxole andpyrazolopyridine groups.

Examples of bicyclic heteroaryl groups containing two fused six memberedrings include but are not limited to quinoline, isoquinoline, chroman,thiochroman, chromene, isochromene, chroman, isochroman, benzodioxan,quinolizine, benzoxazine, benzodiazine, pyridopyridine, quinoxaline,quinazoline, cinnoline, phthalazine, naphthyridine and pteridine groups.

Examples of polycyclic aryl and heteroaryl groups containing an aromaticring and a non-aromatic ring include tetrahydronaphthalene,tetrahydroisoquinoline, tetrahydroquinoline, dihydrobenzthiene,dihydrobenzfuran, 2,3-dihydro-benzo[1,4]dioxine, benzo[1,3]dioxole,4,5,6,7-tetrahydrobenzofuran, indoline and indane groups.

Examples of carbocyclic aryl groups include phenyl, naphthyl, indenyl,and tetrahydronaphthyl groups.

Examples of non-aromatic heterocyclic groups are groups having from 3 to12 ring members, more usually 5 to 10 ring members. Such groups can bemonocyclic or bicyclic, for example, and typically have from 1 to 5heteroatom ring members (more usually 1, 2, 3 or 4 heteroatom ringmembers), usually selected from nitrogen, oxygen and sulphur.

The heterocylic groups can contain, for example, cyclic ether moieties(e.g as in tetrahydrofuran and dioxane), cyclic thioether moieties (e.g.as in tetrahydrothiophene and dithiane), cyclic amine moieties (e.g. asin pyrrolidine), cyclic sulphones (e.g. as in sulfolane and sulfolene),cyclic sulphoxides, cyclic sulphonamides and combinations thereof (e.g.thiomorpholine). Other examples of non-aromatic heterocyclic groupsinclude cyclic amide moieties (e.g. as in pyrrolidone) and cyclic estermoieties (e.g. as in butyrolactone).

Examples of monocyclic non-aromatic heterocyclic groups include 5-, 6-and 7-membered monocyclic heterocyclic groups. Particular examplesinclude morpholine, thiomorpholine and its S-oxide and S,S-dioxide(particularly thiomorpholine), piperidine (e.g. 1-piperidinyl,2-piperidinyl 3-piperidinyl and 4-piperidinyl piperidines such asN-methyl piperidine, piperidone, pyrrolidine (e.g. 1-pyrrolidinyl,2-pyrrolidinyl and 3-pyrrolidinyl), pyrrolidone, azetidine, pyran(2H-pyran or 4H-pyran), dihydrothiophene, dihydropyran, dihydrofuran,dihydrothiazole, tetrahydrofuran, tetrahydrothiophene, dioxane,tetrahydropyran (e.g. 4-tetrahydro pyranyl), imidazoline,imidazolidinone, oxazoline, thiazoline, 2-pyrazoline, pyrazolidine,piperazone, piperazine, and N-alkyl piperazines such as N-methylpiperazine, N-ethyl piperazine and N-isopropylpiperazine.

One sub-group of monocyclic non-aromatic heterocyclic groups includesmorpholine, piperidine (e.g. 1-piperidinyl, 2-piperidinyl 3-piperidinyland 4-piperidinyl), piperidone, pyrrolidine (e.g. 1-pyrrolidinyl,2-pyrrolidinyl and 3-pyrrolidinyl), pyrrolidone, pyran (2H-pyran or4H-pyran), dihydrothiophene, dihydropyran, dihydrofuran,dihydrothiazole, tetrahydrofuran, tetrahydrothiophene, dioxane,tetrahydropyran (e.g. 4-tetrahydro pyranyl), imidazoline,imidazolidinone, oxazoline, thiazoline, 2-pyrazoline, pyrazolidine,piperazone, piperazine, and N-alkyl piperazines such as N-methylpiperazine. In general, preferred non-aromatic heterocyclic groupsinclude piperidine, pyrrolidine, azetidine, morpholine, piperazine andN-alkyl piperazines. A further particular example of a non-aromaticheterocyclic group, which also forms part of the above group ofpreferred non-aromatic heterocyclic groups, is azetidine.

Examples of non-aromatic carbocyclic groups include cycloalkane groupssuch as cyclohexyl and cyclopentyl, cycloalkenyl groups such ascyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl, as well ascyclohexadienyl, cyclooctatetraene, tetrahydronaphthenyl and decalinyl.

Each of the definitions of carbocyclic and heterocyclic groups in thisspecification may optionally exclude any one or any combination of twoor more of the following moieties:

-   -   substituted or unsubstituted pyridone rings;    -   substituted or unsubstituted pyrrolo[1,2-a]pyrimid-4-ones;    -   substituted or unsubstituted pyrazolones.

Where reference is made herein to carbocyclic and heterocyclic groups,the carbocyclic or heterocyclic ring can, unless the context indicatesotherwise, be unsubstituted or substituted by one or more substituentgroups R¹⁰ selected from halogen, hydroxy, trifluoromethyl, cyano,nitro, carboxy, amino, mono- or di-C₁₋₄ hydrocarbylamino, carbocyclicand heterocyclic groups having from 3 to 12 ring members; a groupR^(a)—R^(b) wherein R^(a) is a bond, O, CO, X¹C(X²), C(X²)X¹, X¹C(X²)X¹,S, SO, SO₂, NR^(c), SO₂NR^(c) or NR^(c)SO₂; and R^(b) is selected fromhydrogen, carbocyclic and heterocyclic groups having from 3 to 12 ringmembers, and a C₁₋₈ hydrocarbyl group optionally substituted by one ormore substituents selected from hydroxy, oxo, halogen, cyano, nitro,carboxy, amino, mono- or di-C₁₋₄ hydrocarbylamino, carbocyclic andheterocyclic groups having from 3 to 12 ring members and wherein one ormore carbon atoms of the C₁₋₈ hydrocarbyl group may optionally bereplaced by O, S, SO, SO₂, NR^(c), X¹C(X²), C(X²)X¹ or X¹C(X²)X¹;

-   -   R^(c) is selected from hydrogen and C₁₋₄ hydrocarbyl; and    -   X¹ is O, S or NR^(c) and X² is ═O, ═S or ═NR^(c).

Where the substituent group R¹⁰ comprises or includes a carbocyclic orheterocyclic group, the said carbocyclic or heterocyclic group may beunsubstituted or may itself be substituted with one or more furthersubstituent groups R¹⁰. In one sub-group of compounds of the formula(I), such further substituent groups R¹⁰ may include carbocyclic orheterocyclic groups, which are typically not themselves furthersubstituted. In another sub-group of compounds of the formula (I), thesaid further substituents do not include carbocyclic or heterocyclicgroups but are otherwise selected from the groups listed above in thedefinition of R¹⁰.

The substituents R¹⁰ may be selected such that they contain no more than20 non-hydrogen atoms, for example, no more than 15 non-hydrogen atoms,e.g. no more than 12, or 10, or 9, or 8, or 7, or 6, or 5 non-hydrogenatoms.

Where the carbocyclic and heterocyclic groups have a pair ofsubstituents on adjacent ring atoms, the two substituents may be linkedso as to form a cyclic group. For example, an adjacent pair ofsubstituents on adjacent carbon atoms of a ring may be linked via one ormore heteroatoms and optionally substituted alkylene groups to form afused oxa-, dioxa-, aza-, diaza- or oxa-aza-cycloalkyl group. Examplesof such linked substituent groups include:

Examples of halogen substituents include fluorine, chlorine, bromine andiodine. Fluorine and chlorine are particularly preferred.

In the definition of the compounds of the formula (I) above and as usedhereinafter, the term “hydrocarbyl” is a generic term encompassingaliphatic, alicyclic and aromatic groups having an all-carbon backbone,except where otherwise stated. In certain cases, as defined herein, oneor more of the carbon atoms making up the carbon backbone may bereplaced by a specified atom or group of atoms. Examples of hydrocarbylgroups include alkyl, cycloalkyl, cycloalkenyl, carbocyclic aryl,alkenyl, alkynyl, cycloalkylalkyl, cycloalkenylalkyl, and carbocyclicaralkyl, aralkenyl and aralkynyl groups. Such groups can beunsubstituted or, where stated, can be substituted by one or moresubstituents as defined herein. The examples and preferences expressedbelow apply to each of the hydrocarbyl substituent groups orhydrocarbyl-containing substituent groups referred to in the variousdefinitions of substituents for compounds of the formula (I) unless thecontext indicates otherwise.

Generally by way of example, the hydrocarbyl groups can have up to eightcarbon atoms, unless the context requires otherwise. Within the sub-setof hydrocarbyl groups having 1 to 8 carbon atoms, particular examplesare C₁₋₆ hydrocarbyl groups, such as C₁₋₄ hydrocarbyl groups (e.g. C₁₋₃hydrocarbyl groups or C₁₋₂ hydrocarbyl groups), specific examples beingany individual value or combination of values selected from C₁, C₂, C₃,C₄, C₅, C₆, C₇ and C₈ hydrocarbyl groups.

The term “alkyl” covers both straight chain and branched chain alkylgroups. Examples of alkyl groups include methyl, ethyl, propyl,isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl,2-methyl butyl, 3-methyl butyl, and n-hexyl and its isomers. Within thesub-set of alkyl groups having 1 to 8 carbon atoms, particular examplesare C₁₋₆ alkyl groups, such as C₁₋₄ alkyl groups (e.g. C₁₋₃ alkyl groupsor C₁₋₂ alkyl groups).

Examples of cycloalkyl groups are those derived from cyclopropane,cyclobutane, cyclopentane, cyclohexane and cycloheptane. Within thesub-set of cycloalkyl groups the cycloalkyl group will have from 3 to 8carbon atoms, particular examples being C₃₋₆ cycloalkyl groups.

Examples of alkenyl groups include, but are not limited to, ethenyl(vinyl), 1-propenyl, 2-propenyl(allyl), isopropenyl, butenyl,buta-1,4-dienyl, pentenyl, and hexenyl. Within the sub-set of alkenylgroups the alkenyl group will have 2 to 8 carbon atoms, particularexamples being C₂₋₆ alkenyl groups, such as C₂₋₄ alkenyl groups.

Examples of cycloalkenyl groups include, but are not limited to,cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl andcyclohexenyl. Within the sub-set of cycloalkenyl groups the cycloalkenylgroups have from 3 to 8 carbon atoms, and particular examples are C₃₋₆cycloalkenyl groups.

Examples of alkynyl groups include, but are not limited to, ethynyl and2-propynyl (propargyl) groups. Within the sub-set of alkynyl groupshaving 2 to 8 carbon atoms, particular examples are C₂₋₆ alkynyl groups,such as C₂₋₄ alkynyl groups.

Examples of carbocyclic aryl groups include substituted andunsubstituted phenyl, naphthyl, indane and indene groups.

Examples of cycloalkylalkyl, cycloalkenylalkyl, carbocyclic aralkyl,aralkenyl and aralkynyl groups include phenethyl, benzyl, styryl,phenylethynyl, cyclohexylmethyl, cyclopentylmethyl, cyclobutylmethyl,cyclopropylmethyl and cyclopentenylmethyl groups.

When present, and where stated, a hydrocarbyl group can be optionallysubstituted by one or more substituents selected from hydroxy, oxo,alkoxy, carboxy, halogen, cyano, nitro, amino, mono- or di-C₁₋₄hydrocarbylamino, and monocyclic or bicyclic carbocyclic andheterocyclic groups having from 3 to 12 (typically 3 to 10 and moreusually 5 to 10) ring members. Preferred substituents include halogensuch as fluorine. Thus, for example, the substituted hydrocarbyl groupcan be a partially fluorinated or perfluorinated group such asdifluoromethyl or trifluoromethyl. In one embodiment preferredsubstituents include monocyclic carbocyclic and heterocyclic groupshaving 3-7 ring members.

Where stated, one or more carbon atoms of a hydrocarbyl group mayoptionally be replaced by O, S, SO, SO₂, NR^(c), X¹C(X²), C(X²)X¹ orX¹C(X²)X¹ (or a sub-group thereof) wherein X¹ and X² are as hereinbeforedefined, provided that at least one carbon atom of the hydrocarbyl groupremains. For example, 1, 2, 3 or 4 carbon atoms of the hydrocarbyl groupmay be replaced by one of the atoms or groups listed, and the replacingatoms or groups may be the same or different. In general, the number oflinear or backbone carbon atoms replaced will correspond to the numberof linear or backbone atoms in the group replacing them. Examples ofgroups in which one or more carbon atom of the hydrocarbyl group havebeen replaced by a replacement atom or group as defined above includeethers and thioethers (C replaced by O or S), amides, esters, thioamidesand thioesters (C—C replaced by X¹C(X²) or C(X²)X¹), sulphones andsulphoxides (C replaced by SO or SO₂), amines (C replaced by NR^(c)).Further examples include ureas, carbonates and carbamates (C—C—Creplaced by X¹C(X²)X¹).

Where an amino group has two hydrocarbyl substituents, they may,together with the nitrogen atom to which they are attached, andoptionally with another heteroatom such as nitrogen, sulphur, or oxygen,link to form a ring structure of 4 to 7 ring members.

The definition “R^(a)—R^(b)” as used herein, either with regard tosubstituents present on a carbocyclic or heterocyclic moiety, or withregard to other substituents present at other locations on the compoundsof the formula (I), includes inter alia compounds wherein R^(a) isselected from a bond, O, CO, OC(O), SC(O), NR^(c)C(O), OC(S), SC(S),NR^(c)C(S), OC(NR^(c)), SC(NR^(c)), NR^(c)C(NR^(c)), C(O)O, C(O)S,C(O)NR^(c), C(S)O, C(S)S, C(S)NR^(c), C(NR^(c))O, C(NR^(c))S,C(NR^(c))NR^(c), OC(O)O, SC(O)O, NR^(c)C(O)O, OC(S)O, SC(S)O,NR^(c)C(S)O, OC(NR^(c))O, SC(NR^(c))O, NR^(c)C(NR^(c))O, OC(O)S, SC(O)S,NR^(c)C(O)S, OC(S)S, SC(S)S, NR^(c)C(S)S, OC(NR^(c))S, SC(NR^(c))S,NR^(c)C(NR^(c))S, OC(O)NR^(c), SC(O)NR^(c), NR^(c)C(O)NR^(c),OC(S)NR^(c), SC(S)NR^(c), NR^(c)C(S)NR^(c), OC(NR^(c))NR^(c),SC(NR^(c))NR^(c), NR^(c)C(NR^(c)NR^(c), S, SO, SO₂, NR^(c), SO₂NR^(c)and NR^(c)SO₂ wherein R^(c) is as hereinbefore defined.

The moiety R^(b) can be hydrogen or it can be a group selected fromcarbocyclic and heterocyclic groups having from 3 to 12 ring members(typically 3 to 10 and more usually from 5 to 10), and a C₁₋₈hydrocarbyl group optionally substituted as hereinbefore defined.Examples of hydrocarbyl, carbocyclic and heterocyclic groups are as setout above.

When R^(a) is O and R^(b) is a C₁₋₈ hydrocarbyl group, R^(a) and R^(b)together form a hydrocarbyloxy group. Preferred hydrocarbyloxy groupsinclude saturated hydrocarbyloxy such as alkoxy (e.g. C₁₋₆ alkoxy, moreusually C₁₋₄ alkoxy such as ethoxy and methoxy, particularly methoxy),cycloalkoxy (e.g. C₃₋₆ cycloalkoxy such as cyclopropyloxy,cyclobutyloxy, cyclopentyloxy and cyclohexyloxy) and cycloalkyalkoxy(e.g. C₃₋₆ cycloalkyl-C₁₋₂ alkoxy such as cyclopropylmethoxy).

The hydrocarbyloxy groups can be substituted by various substituents asdefined herein. For example, the alkoxy groups can be substituted byhalogen (e.g. as in difluoromethoxy and trifluoromethoxy), hydroxy (e.g.as in hydroxyethoxy), C₁₋₂ alkoxy (e.g. as in methoxyethoxy),hydroxy-C₁₋₂ alkyl (as in hydroxyethoxyethoxy) or a cyclic group (e.g. acycloalkyl group or non-aromatic heterocyclic group as hereinbeforedefined). Examples of alkoxy groups bearing a non-aromatic heterocyclicgroup as a substituent are those in which the heterocyclic group is asaturated cyclic amine such as morpholine, piperidine, pyrrolidine,piperazine, C₁₋₄-alkyl-piperazines, C₃₋₇-cycloalkyl-piperazines,tetrahydropyran or tetrahydrofuran and the alkoxy group is a C₁₋₄ alkoxygroup, more typically a C₁₋₃ alkoxy group such as methoxy, ethoxy orn-propoxy.

Alkoxy groups may be substituted by, for example, a monocyclic groupsuch as pyrrolidine, piperidine, morpholine and piperazine andN-substituted derivatives thereof such as N-benzyl, N—C₁₋₄ acyl andN—C₁₋₄ alkoxycarbonyl. Particular examples include pyrrolidinoethoxy,piperidinoethoxy and piperazinoethoxy.

When R^(a) is a bond and R^(b) is a C₁₋₈ hydrocarbyl group, examples ofhydrocarbyl groups R^(a)—R^(b) are as hereinbefore defined. Thehydrocarbyl groups may be saturated groups such as cycloalkyl and alkyland particular examples of such groups include methyl, ethyl andcyclopropyl. The hydrocarbyl (e.g. alkyl) groups can be substituted byvarious groups and atoms as defined herein. Examples of substitutedalkyl groups include alkyl groups substituted by one or more halogenatoms such as fluorine and chlorine (particular examples includingbromoethyl, chloroethyl, difluoromethyl, 2,2,2-trifluoroethyl andperfluoroalkyl groups such as trifluoromethyl), or hydroxy (e.g.hydroxymethyl and hydroxyethyl), C₁₋₈ acyloxy (e.g. acetoxymethyl andbenzyloxymethyl), amino and mono- and dialkylamino (e.g. aminoethyl,methylaminoethyl, dimethylaminomethyl, dimethylaminoethyl andtert-butylaminomethyl), alkoxy (e.g. C₁₋₂ alkoxy such as methoxy—as inmethoxyethyl), and cyclic groups such as cycloalkyl groups, aryl groups,heteroaryl groups and non-aromatic heterocyclic groups as hereinbeforedefined).

Particular examples of alkyl groups substituted by a cyclic group arethose wherein the cyclic group is a saturated cyclic amine such asmorpholine, piperidine, pyrrolidine, piperazine, C₁₋₄-alkyl-piperazines,C₃₋₇-cycloalkyl-piperazines, tetrahydropyran or tetrahydrofuran and thealkyl group is a C₁₋₄ alkyl group, more typically a C₁₋₃ alkyl groupsuch as methyl, ethyl or n-propyl. Specific examples of alkyl groupssubstituted by a cyclic group include pyrrolidinomethyl,pyrrolidinopropyl, morpholinomethyl, morpholinoethyl, morpholinopropyl,piperidinylmethyl, piperazinomethyl and N-substituted forms thereof asdefined herein.

Particular examples of alkyl groups substituted by aryl groups andheteroaryl groups include benzyl, phenethyl and pyridylmethyl groups.

When R⁸ is SO₂NR^(c), R^(b) can be, for example, hydrogen or anoptionally substituted C₁₋₈ hydrocarbyl group, or a carbocyclic orheterocyclic group. Examples of R^(a)—R^(b) where R^(a) is SO₂NR^(c)include aminosulphonyl, C₁₋₄ alkylaminosulphonyl and di-C₁₋₄alkylaminosulphonyl groups, and sulphonamides formed from a cyclic aminogroup such as piperidine, morpholine, pyrrolidine, or an optionallyN-substituted piperazine such as N-methyl piperazine.

Examples of groups R^(a)—R^(b) where R^(a) is SO₂ includealkylsulphonyl, heteroarylsulphonyl and arylsulphonyl groups,particularly monocyclic aryl and heteroaryl sulphonyl groups. Particularexamples include methylsulphonyl, phenylsulphonyl and toluenesulphonyl.

When R^(a) is NR^(c), R^(b) can be, for example, hydrogen or anoptionally substituted C₁₋₈ hydrocarbyl group, or a carbocyclic orheterocyclic group. Examples of R^(a)—R^(b) where R^(a) is NR^(c)include amino, C₁₋₄ alkylamino (e.g. methylamino, ethylamino,propylamino, isopropylamino, tert-butylamino), di-C₁₋₄ alkylamino (e.g.dimethylamino and diethylamino) and cycloalkylamino (e.g.cyclopropylamino, cyclopentylamino and cyclohexylamino).

Specific Embodiments of and Preferences for A, E, R¹ to R⁵ and R⁹

The Group “A”

In formula (I), A is a saturated hydrocarbon linker group containingfrom 1 to 7 carbon atoms, the linker group having a maximum chain lengthof 5 atoms extending between R¹ and NR²R³ and a maximum chain length of4 atoms extending between E and NR²R³. Within these constraints, themoieties E and R¹ can each be attached at any location on the group A.

The term “maximum chain length” as used herein refers to the number ofatoms lying directly between the two moieties in question, and does nottake into account any branching in the chain or any hydrogen atoms thatmay be present. For example, in the structure A shown below:

the chain length between R¹ and NR²R³ is 3 atoms whereas the chainlength between E and NR²R³ is 2 atoms.

In general it is presently preferred that the linker group has a maximumchain length of 3 atoms (for example 1 or 2 atoms).

In one embodiment, the linker group has a chain length of 1 atomextending between R¹ and NR²R³.

In another embodiment, the linker group has a chain length of 2 atomsextending between R¹ and NR²R³.

In a further embodiment, the linker group has a chain length of 3 atomsextending between R¹ and NR²R³.

It is preferred that the linker group has a maximum chain length of 3atoms extending between E and NR²R³.

In one particularly preferred group of compounds, the linker group has achain length of 2 or 3 atoms extending between R¹ and NR²R³ and a chainlength of 2 or 3 atoms extending between E and NR²R³.

One of the carbon atoms in the linker group may optionally be replacedby an oxygen or nitrogen atom.

When present, the nitrogen atom may be linked directly to the group E.

In one embodiment, the carbon atom to which the group R¹ is attached isreplaced by an oxygen atom.

In another embodiment, R¹ and E are attached to the same carbon atom ofthe linker group, and a carbon atom in the chain extending between E andNR²R³ is replaced by an oxygen atom.

When a nitrogen atom or oxygen atom are present, it is preferred thatthe nitrogen or oxygen atom and the NR²R³ group are spaced apart by atleast two intervening carbon atoms.

In one particular group of compounds within formula (I), the linker atomlinked directly to the group E is a carbon atom and the linker group Ahas an all-carbon skeleton.

The carbon atoms of the linker group A may optionally bear one or moresubstituents selected from oxo, fluorine and hydroxy, provided that thehydroxy group is not located at a carbon atom a with respect to theNR²R³ group, and provided also that the oxo group is located at a carbonatom a with respect to the NR²R³ group. Typically, the hydroxy group, ifpresent, is located at a position β with respect to the NR²R³ group. Ingeneral, no more than one hydroxy group will be present. Where fluorineis present, it may be present as a single fluorine substituent or may bepresent in a difluoromethylene or trifluoromethyl group, for example. Inone embodiment, a fluorine atom is located at a position β with respectto the NR²R³ group.

It will be appreciated that that when an oxo group is present at thecarbon atom adjacent the NR²R³ group, the compound of the formula (I)will be an amide.

In one embodiment of the invention, no fluorine atoms are present in thelinker group A.

In another embodiment of the invention, no hydroxy groups are present inthe linker group A.

In a further embodiment, no oxo group is present in the linker group A.

In one group of compounds of the formula (I) neither hydroxy groups norfluorine atoms are present in the linker group A, e.g. the linker groupA is unsubstituted.

Preferably, when a carbon atom in the linker group A is replaced by anitrogen atom, the group A bears no more than one hydroxy substituentand more preferably bears no hydroxy substituents.

When there is a chain length of four atoms between E and NR²R³, it ispreferred that the linker group A contains no nitrogen atoms and morepreferably has an all carbon skeleton.

In order to modify the susceptibility of the compounds to metabolicdegradation in vivo, the linker group A can have a branchedconfiguration at the carbon atom attached to the NR²R³ group. Forexample, the carbon atom attached to the NR²R³ group can be attached toa pair of gem-dimethyl groups.

In one particular group of compounds of the formula (I), the portionR¹-A-NR²R³ of the compound is represented by the formulaR¹-(G)_(k)-(CH₂)_(m)—W—O_(b)—(CH₂)_(n)—(CR⁶R⁷)_(p)—NR²R³ wherein G isNH, NMe or O; W is attached to the group E and is selected from(CH₂)_(j)—CR²⁰, (CH₂)_(j)—N and (NH)_(j)—CH; b is 0 or 1, j is 0 or 1, kis 0 or 1, m is 0 or 1, n is 0, 1, 2, or 3 and p is 0 or 1; the sum of band k is 0 or 1; the sum of j, k, m, n and p does not exceed 4; R⁶ andR⁷ are the same or different and are selected from methyl and ethyl, orCR⁶R⁷ forms a cyclopropyl group; and R²⁰ is selected from hydrogen,methyl, hydroxy and fluorine;

In another sub-group of compounds of the formula (I), the portionR¹-A-NR²R³ of the compound is represented by the formulaR¹-(G)_(k)-(CH₂)_(m)—X—(CH₂)_(n)—(CR⁸R⁷)_(p)—NR²R³ wherein G is NH, NMeor O; X is attached to the group E and is selected from (CH₂)_(j)—CH,(CH₂)_(j)—N and (NH)_(j)—CH; j is 0 or 1, k is 0 or 1, m is 0 or 1, n is0, 1, 2, or 3 and p is 0 or 1, and the sum of j, k, m, n and p does notexceed 4; and R⁶ and R⁷ are the same or different and are selected frommethyl and ethyl, or CR⁶R⁷ forms a cyclopropyl group.

A particular group CR⁶R⁷ is C(CH₃)₂.

Preferably X is (CH₂)_(j)—CH.

Particular configurations where the portion R¹-A-NR²R³ of the compoundis represented by the formulaR¹-(G)_(k)-(CH₂)_(m)—X—(CH₂)_(n)—(CR⁶R⁷)_(p)—NR²R³ are those wherein:

-   -   k is 0, m is 0 or 1, n is 0, 1, 2 or 3 and p is 0.    -   k is 0, m is 0 or 1, n is 0, 1 or 2 and p is 1.    -   X is (CH₂)_(j)—CH, k is 1, m is 0, n is 0, 1, 2 or 3 and p is 0.    -   X is (CH₂)_(j)—CH, k is 1, m is 0, n is 0, 1 or 2 and p is 1.    -   X is (CH₂)_(j)—CH, G is O, k is 1, m is 0, n is 0, 1, 2 or 3 and        p is 0.

Particular configurations wherein the portion R¹-A-NR²R³ of the compoundis represented by the formulaR¹-(G)_(k)-(CH₂)_(m)—W—O_(b)—(CH₂)_(n)—(CR⁶R⁷)_(p)—NR²R³ are thosewherein:

-   -   k is 0, m is 0, W is (CH₂)_(j)—CR²⁰, j is 0, R²⁰ is hydrogen, b        is 1, n is 2 and p is 0.    -   k is 0, m is 0, W is (CH₂)_(j)—CR²⁰, j is 0, R²⁰ is hydroxy, b        is 0, n is 1 and p is 0.    -   k is 0, m is 0, W is (CH₂)_(j)—CR²⁰, j is 0, R²⁰ is methyl, b is        0, n is 1 and p is 0.    -   k is 0, m is 0, W is (CH₂)_(j)—CR²⁰, j is 0, R²⁰ is fluorine, b        is 0, n is 1 and p is 0.

In one preferred configuration, the portion R¹-A-NR²R³ of the compoundis represented by the formula R¹—X—(CH₂)_(n)—NR²R³ wherein X is attachedto the group E and is a group CH, and n is 2.

Particular examples of the linker group A, together with their points ofattachment to the groups R¹, E and NR²R³, are shown in Table 1 below.

TABLE 1

Currently preferred groups include A1, A2, A3, A6, A10, A11, A22 andA23.

One particular set of groups includes A1, A2, A3, A10 and A11.

A further particular set of groups includes A2 and A11.

Another particular set of groups includes A6, A22 and A23.

A further set of groups includes A1, A2 and A3.

In group A2, the asterisk designates a chiral centre. Compounds havingthe R configuration at this chiral centre represent one preferredsub-group of compounds of the invention.

R¹

The group R¹ is an aryl or heteroaryl group and may be selected from thelist of such groups set out in the section headed General Preferencesand Definitions.

R¹ can be monocyclic or bicyclic and, in one preferred embodiment, ismonocyclic. Particular examples of monocyclic aryl and heteroaryl groupsare six membered aryl and heteroaryl groups containing up to 2 nitrogenring members, and five membered heteroaryl groups containing up to 3heteroatom ring members selected from O, S and N.

Examples of such groups include phenyl, naphthyl, thienyl, furan,pyrimidine and pyridine, with phenyl being presently preferred.

The group R¹ can be unsubstituted or substituted by up to 5substituents, and examples of substituents are those listed in group R¹⁰above.

Particular substituents include hydroxy; C₁₋₄ acyloxy; fluorine;chlorine; bromine; trifluoromethyl; cyano; CONH₂; nitro; C₁₋₄hydrocarbyloxy and C₁₋₄ hydrocarbyl each optionally substituted by C₁₋₂alkoxy, carboxy or hydroxy; C₁₋₄ acylamino; benzoylamino;pyrrolidinocarbonyl; piperidinocarbonyl; morpholinocarbonyl;piperazinocarbonyl; five and six membered heteroaryl and heteroaryloxygroups containing one or two heteroatoms selected from N, O and S;phenyl; phenyl-C₁₋₄ alkyl; phenyl-C₁₋₄ alkoxy; heteroaryl-C₁₋₄ alkyl;heteroaryl-C₁₋₄ alkoxy and phenoxy, wherein the heteroaryl,heteroaryloxy, phenyl, phenyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkoxy,heteroaryl-C₁₋₄ alkyl, heteroaryl-C₁₋₄ alkoxy and phenoxy groups areeach optionally substituted with 1, 2 or 3 substituents selected fromC₁₋₂ acyloxy, fluorine, chlorine, bromine, trifluoromethyl, cyano,CONH₂, C₁₋₂ hydrocarbyloxy and C₁₋₂ hydrocarbyl each optionallysubstituted by methoxy or hydroxy.

Preferred substituents include hydroxy; C₁₋₄ acyloxy; fluorine;chlorine; bromine; trifluoromethyl; cyano; C₁₋₄ hydrocarbyloxy and C₁₋₄hydrocarbyl each optionally substituted by C₁₋₂ alkoxy or hydroxy; C₁₋₄acylamino; benzoylamino; pyrrolidinocarbonyl; piperidinocarbonyl;morpholinocarbonyl; piperazinocarbonyl; five and six membered heteroarylgroups containing one or two heteroatoms selected from N, O and S, theheteroaryl groups being optionally substituted by one or more C₁₋₄ alkylsubstituents; phenyl; pyridyl; and phenoxy wherein the phenyl, pyridyland phenoxy groups are each optionally substituted with 1, 2 or 3substituents selected from C₁₋₂ acyloxy, fluorine, chlorine, bromine,trifluoromethyl, cyano, C₁₋₂ hydrocarbyloxy and C₁₋₂ hydrocarbyl eachoptionally substituted by methoxy or hydroxy.

In one sub-group of compounds, the substituents for R¹ are chosen fromhydroxy; C₁₋₄ acyloxy; fluorine; chlorine; bromine; trifluoromethyl;cyano; C₁₋₄ hydrocarbyloxy and C₁₋₄ hydrocarbyl each optionallysubstituted by C₁₋₂ alkoxy or hydroxy.

Although up to 5 substituents may be present, more typically there are0, 1, 2, 3 or 4 substituents, preferably 0, 1, 2 or 3, and morepreferably 0, 1 or 2.

In one embodiment, the group R¹ is unsubstituted or substituted by up to5 substituents selected from hydroxy; C₁₋₄ acyloxy; fluorine; chlorine;bromine; trifluoromethyl; cyano; C₁₋₄ hydrocarbyloxy and C₁₋₄hydrocarbyl each optionally substituted by C₁₋₂ alkoxy or hydroxy.

In a further embodiment, the group R¹ can have one or two substituentsselected from hydroxy, fluorine, chlorine, cyano, phenyloxy,pyrazinyloxy, benzyloxy, methyl and methoxy.

In another embodiment, the group R¹ can have one or two substituentsselected from fluorine, chlorine, trifluoromethyl, methyl and methoxy.

When R¹ is a phenyl group, particular examples of substituentcombinations include mono-chlorophenyl and dichlorophenyl.

Further examples of substituent combinations include those wherein R¹ ishydroxyphenyl, fluorochlorophenyl, cyanophenyl, methoxyphenyl,methoxy-chlorophenyl, fluorophenyl, difluorophenyl, phenoxyphenyl,pyrazinyloxyphenyl or benzyloxyphenyl.

When R¹ is a six membered aryl or heteroaryl group, a substituent mayadvantageously be present at the para position on the six-membered ring.Where a substituent is present at the pare position, it is preferablylarger in size than a fluorine atom.

R² and R³

In one group of compounds of the formula (I), R² and R³ areindependently selected from hydrogen, C₁₋₄ hydrocarbyl and C₁₋₄ acylwherein the hydrocarbyl and acyl moieties are optionally substituted byone or more substituents selected from fluorine, hydroxy, amino,methylamino, dimethylamino and methoxy.

When the hydrocarbyl moiety is substituted by a hydroxy, amino,methylamino, dimethylamino or methoxy group, typically there are atleast two carbon atoms between the substituent and the nitrogen atom ofthe group NR²R³. Particular examples of substituted hydrocarbyl groupsare hydroxyethyl and hydroxypropyl.

In another group of compounds of the invention, R² and R³ areindependently selected from hydrogen, C₁₋₄ hydrocarbyl and C₁₋₄ acyl.

Typically the hydrocarbyl group, whether substituted or unsubstituted,is an alkyl group, more usually a C₁, C₂ or C₃ alkyl group, andpreferably a methyl group. In one particular sub-group of compounds, R²and R³ are independently selected from hydrogen and methyl and henceNR²R³ can be an amino, methylamino or dimethylamino group. In oneparticular embodiment, NR²R³ can be an amino group. In anotherparticular embodiment, NR²R³ can be a methylamino group.

In an alternative embodiment, the C₁₋₄ hydrocarbyl group can be acyclopropyl, cyclopropylmethyl or cyclobutyl group.

In another group of compounds, R² and R³ together with the nitrogen atomto which they are attached form a cyclic group selected from animidazole group and a saturated monocyclic heterocyclic group having 4-7ring members and optionally containing a second heteroatom ring memberselected from 0 and N.

In a further group of compounds, R² and R³ together with the nitrogenatom to which they are attached form a saturated monocyclic heterocyclicgroup having 4-7 ring members and optionally containing a secondheteroatom ring member selected from O and N.

The saturated monocyclic heterocyclic group can be unsubstituted orsubstituted by one or more substituents R¹⁰ as defined above in theGeneral Preferences and Definitions section of this application.Typically, however, any substituents on the heterocyclic group will berelatively small substituents such as C₁₋₄ hydrocarbyl (e.g. methyl,ethyl, n-propyl, i-propyl, cyclopropyl, n-butyl, sec-butyl andtest-butyl), fluorine, chlorine, hydroxy, amino, methylamino, ethylaminoand dimethylamino. Particular substituents are methyl groups.

The saturated monocyclic ring can be an azacycloalkyl group such as anazetidine, pyrrolidine, piperidine or azepane ring, and such rings aretypically unsubstituted.

Alternatively, the saturated monocyclic ring can contain an additionalheteroatom selected from O and N, and examples of such groups includemorpholine and piperazine. Where an additional N atom is present in thering, this can form part of an NH group or an N—C₁₋₄alkyl group such asan N-methyl, N-ethyl, N-propyl or N-isopropyl group.

Where NR²R³ forms an imidazole group, the imidazole group can beunsubstituted or substituted, for example by one or more relativelysmall substituents such as C₁₋₄ hydrocarbyl (e.g. methyl, ethyl, propyl,cyclopropyl and butyl), fluorine, chlorine, hydroxy, amino, methylamino,ethylamino and dimethylamino. Particular substituents are methyl groups.

In a further group of compounds, one of R² and R³ together with thenitrogen atom to which they are attached and one or more atoms from thelinker group A form a saturated monocyclic heterocyclic group having 4-7ring members and optionally containing a second heteroatom ring memberselected from O and N.

Examples of such compounds include compounds wherein NR²R³ and A form aunit of the formula:

where t and u are each 0, 1, 2 or 3 provided that the sum oft and ufalls within the range of 2 to 4.

Further examples of such compounds include compounds wherein NR²R³ and Aform a cyclic group of the formula:

where v and w are each 0, 1, 2 or 3 provided that the sum of v and wfalls within the range of 2 to 5. Particular examples of cycliccompounds are those in which v and w are both 2.

Further examples of such compounds include compounds wherein NR²R³ and Aform a cyclic group of the formula:

where x and w are each 0, 1, 2 or 3 provided that the sum of x and wfalls within the range of 2 to 4. Particular examples of cycliccompounds are those in which x is 2 and w is 1.

R⁴

In formula (I), R⁴ is selected from hydrogen, halogen, C₁₋₅ saturatedhydrocarbyl, C₁₋₅ saturated hydrocarbyloxy, cyano, and CF₃.

More typically, R⁴ is selected from hydrogen, halogen, C₁₋₅ saturatedhydrocarbyl, cyano and CF₃. Preferred values for R⁴ include hydrogen andmethyl. In a particular embodiment, R⁴ is hydrogen.

R⁵

In formula (I), R⁵ is selected from hydrogen, halogen, C₁₋₅ saturatedhydrocarbyl, C₁₋₅ saturated hydrocarbyloxy, cyano, CONH₂, CONHR⁹, CF₃,NH₂, NHCOR⁹ and NHCONHR⁹; NHCONHR⁹ where R⁹ is a group R^(9a) or(CH₂)R^(9a), wherein R^(9a) is an optionally substituted monocyclic orbicyclic group which may be carbocyclic or heterocyclic.

Examples of carbocyclic and heterocyclic groups are set out above in theGeneral Preferences and Definitions section.

Typically the carbocyclic and heterocyclic groups are monocyclic.

Preferably the carbocyclic and heterocyclic groups are aromatic.

Particular examples of the group R⁹ are optionally substituted phenyl orbenzyl.

Preferably, R⁵ is selected from selected from hydrogen, halogen, C₁₋₅saturated hydrocarbyl, cyano, CONH₂, CONHR⁹, CF₃, NH₂, NHCOR⁹ andNHCONHR⁹ where R⁹ is optionally substituted phenyl or benzyl.

More preferably, R⁵ is selected from selected from hydrogen, halogen,C₁₋₅ saturated hydrocarbyl, cyano, CF₃, NH₂, NHCOR⁹ and NHCONHR⁹ whereR⁹ is optionally substituted phenyl or benzyl.

The group R⁹ is typically unsubstituted phenyl or benzyl, or phenyl orbenzyl substituted by 1, 2 or 3 substituents selected from halogen;hydroxy; trifluoromethyl; cyano; carboxy; C₁₋₄alkoxycarbonyl; C₁₋₄acyloxy; amino; mono- or di-C₁₋₄ alkylamino; C₁₋₄ alkyl optionallysubstituted by halogen, hydroxy or C₁₋₂ alkoxy; C₁₋₄ alkoxy optionallysubstituted by halogen, hydroxy or C₁₋₂ alkoxy; phenyl, five and sixmembered heteroaryl groups containing up to 3 heteroatoms selected fromO, N and S; and saturated carbocyclic and heterocyclic groups containingup to 2 heteroatoms selected from O, S and N.

Particular examples of the moiety R⁵ include hydrogen, fluorine,chlorine, bromine, methyl, ethyl, hydroxyethyl, methoxymethyl, cyano,CF₃, NH₂, NHCOR^(9b) and NHCONHR^(9b) where R^(9b) is phenyl or benzyloptionally substituted by hydroxy, C₁₋₄ acyloxy, fluorine, chlorine,bromine, trifluoromethyl, cyano, C₁₋₄ hydrocarbyloxy (e.g. alkoxy) andC₁₋₄ hydrocarbyl (e.g. alkyl) optionally substituted by C₁₋₂ alkoxy orhydroxy.

Preferred examples of R⁵ include hydrogen, methyl and cyano. PreferablyR⁵ is hydrogen or methyl.

The Group “E”

In formula (I), E is a monocyclic or bicyclic carbocyclic orheterocyclic group and can be selected from the groups set out above inthe section headed General Preferences and Definitions.

Preferred groups E are monocyclic and bicyclic aryl and heteroarylgroups and, in particular, groups containing a six membered aromatic orheteroaromatic ring such as a phenyl, pyridine, pyrazine, pyridazine orpyrimidine ring, more particularly a phenyl, pyridine, pyrazine orpyrimidine ring, and more preferably a pyridine or phenyl ring.

Examples of bicyclic groups include benzo-fused and pyrido-fused groupswherein the group A and the pyrazole ring are both attached to thebenzo- or pyrido-moiety.

In one embodiment, E is a monocyclic group.

Particular examples of monocyclic groups include monocyclic aryl andheteroaryl groups such as phenyl, thiophene, furan, pyrimidine, pyrazineand pyridine, phenyl being presently preferred.

One subset of monocyclic aryl and heteroaryl groups comprises phenyl,thiophene, furan, pyrimidine and pyridine.

Examples of non-aromatic monocyclic groups include cycloalkanes such ascyclohexane and cyclopentane, and nitrogen-containing rings such aspiperazine and piperazone.

It is preferred that the group A and the pyrazole group are not attachedto adjacent ring members of the group E. For example, the pyrazole groupcan be attached to the group E in a meta or para relative orientation.

Examples of such groups E include 1,4-phenylene, 1,3-phenylene,2,5-pyridylene and 2,4-pyridylene, 1,4-piperazinyl, and 1,4-piperazonyl.Further examples include 1,3-disubstituted five membered rings.

The groups E can be unsubstituted or can have up to 4 substituents R⁸which may be selected from the group R¹⁰ as hereinbefore defined. Moretypically however, the substituents R⁸ are selected from hydroxy; oxo(when E is non-aromatic); halogen (e.g. chlorine and bromine);trifluoromethyl; cyano; C₁₋₄ hydrocarbyloxy optionally substituted byC₁₋₂ alkoxy or hydroxy; and C₁₋₄ hydrocarbyl optionally substituted byC₁₋₂ alkoxy or hydroxy.

Preferably there are 0-3 substituents, more preferably 0-2 substituents,for example 0 or 1 substituent. In one embodiment, the group E isunsubstituted.

E may be other than:

-   -   a substituted pyridone group;    -   a substituted thiazole group;    -   a substituted or unsubstituted pyrazole or pyrazolone group;    -   a substituted or unsubstituted bicyclic fused pyrazole group;    -   a phenyl ring fused to a thiophene ring or a six membered        nitrogen-containing heteroaryl ring fused to a thiophene ring;    -   a substituted or unsubstituted piperazine group;

The group E can be an aryl or heteroaryl group having five or sixmembers and containing up to three heteroatoms selected from O, N and S,the group E being represented by the formula:

where * denotes the point of attachment to the pyrazole group, and “a”denotes the attachment of the group A;

r is 0, 1 or 2;

U is selected from N and CR^(12a); and

V is selected from N and CR^(12b); where R^(12a) and R^(12b) are thesame or different and each is hydrogen or a substituent containing up toten atoms selected from C, N, O, F, Cl and S provided that the totalnumber of non-hydrogen atoms present in R^(12a) and R^(12b) togetherdoes not exceed ten;

or R^(12a) and R^(12b) together with the carbon atoms to which they areattached form an unsubstituted five or six membered saturated orunsaturated ring containing up to two heteroatoms selected from O and N;and

R¹⁰ is as hereinbefore defined.

In one preferred group of compounds, E is a group:

where * denotes the point of attachment to the pyrazole group, and “a”denotes the attachment of the group A; P, Q and T are the same ordifferent and are selected from N, CH and NCR¹⁰, provided that the groupA is attached to a carbon atom; and U, V and R¹⁰ are as hereinbeforedefined.

Examples of R^(12a) and R^(12b) include hydrogen and substituent groupsR¹⁰ as hereinbefore defined having no more than ten non-hydrogen atoms.Particular examples of R^(12a) and R^(12b) include methyl, ethyl,propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, fluorine,chlorine, methoxy, trifluoromethyl, hydroxymethyl, hydroxyethyl,methoxymethyl, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethyl,cyano, amino, methylamino, dimethylamino, CONH₂, CO₂Et, CO₂H, acetamido,azetidinyl, pyrrolidino, piperidine, piperazino, morpholino,methylsulphonyl, aminosulphonyl, mesylamino and trifluoroacetamido.

Preferably, when U is CR^(12a) and/or V is CR^(12b) the atoms or groupsin R^(12a) and R^(12b) that are directly attached to the carbon atomring members C are selected from H, O (e.g. as in methoxy), NH (e.g. asin amino and methylamino) and CH₂ (e.g. as in methyl and ethyl).

Particular examples of the linker group E, together with their points ofattachment to the group A (^(a)) and the pyrazole ring (*) are shown inTable 2 below.

TABLE 2

In the table, the substituent group R¹³ is selected from methyl,chlorine, fluorine and trifluoromethyl.

The following optional exclusions may apply to the definition of E inany of formulae (I), (Ia), (Ib), (II), (III), (IV) and (V) and anysub-groups or sub-definitions thereof as defined herein:

-   -   E may be other than a phenyl group having a sulphur atom        attached to the position para with respect to the pyrazole        group.    -   E may be other than a substituted or unsubstituted        benzimidazole, benzoxazole or benzthiazole group.

One sub-group of compounds of the formula (I) has the general formula(II):

wherein the group A is attached to the meta or para position of thebenzene ring, q is 0-4; R¹, R², R³, R⁴ and R⁵ are as defined herein inrespect of formula (I) and sub-groups, examples and preferences thereof;and R⁸ is a substituent group as hereinbefore defined. In formula (II),q is preferably 0, 1 or 2, more preferably 0 or 1 and most preferably 0.Preferably the group A is attached to the para position of the benzenering.

Within formula (II), one particular sub-group of compounds of theinvention is represented by the formula (III):

where A′ is the residue of the group A and R¹ to R⁵ are as definedherein.

Within formula (III), one preferred group of compounds is presented bythe formula (IV):

wherein z is 0, 1 or 2, R²⁰ is selected from hydrogen, methyl, hydroxyand fluorine and R¹ to R⁵ are as defined herein, provided that when z is0, R²⁰ is other than hydroxy.

Another group of compounds within formula (III) is represented byformula (V):

wherein and R¹ and R³ to R⁵ are as defined herein.

In formula (V), R³ is preferably selected from hydrogen and C₁₋₄hydrocarbyl, for example C₁₋₄ alkyl such as methyl, ethyl and isopropyl.More preferably R³ is hydrogen.

In each of formulae (II) to (V), R¹ is preferably an optionallysubstituted phenyl group as defined herein.

In another sub-group of compounds of the invention, A is a saturatedhydrocarbon linker group containing from 1 to 7 carbon atoms, the linkergroup having a maximum chain length of 5 atoms extending between R¹ andNR²R³ and a maximum chain length of 4 atoms extending between E andNR²R³, wherein one of the carbon atoms in the linker group mayoptionally be replaced by an oxygen or nitrogen atom; and wherein thecarbon atoms of the linker group A may optionally bear one or moresubstituents selected from fluorine and hydroxy, provided that thehydroxy group when present is not located at a carbon atom a withrespect to the NR²R³ group; and

R⁵ is selected from selected from hydrogen, C₁₋₅ saturated hydrocarbyl,cyano, CONH₂, CF₃, NH₂, NHCOR⁹ and NHCONHR⁹.

For the avoidance of doubt, it is to be understood that each general andspecific preference, embodiment and example of the groups R¹ may becombined with each general and specific preference, embodiment andexample of the groups R² and/or R³ and/or R⁴ and/or R⁵ and/or R⁹ andthat all such combinations are embraced by this application.

The various functional groups and substituents making up the compoundsof the formula (I) are typically chosen such that the molecular weightof the compound of the formula (I) does not exceed 1000. More usually,the molecular weight of the compound will be less than 750, for exampleless than 700, or less than 650, or less than 600, or less than 550.More preferably, the molecular weight is less than 525 and, for example,is 500 or less.

Particular compounds of the invention are as illustrated in the examplesbelow and are selected from:

-   2-phenyl-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethylamine;-   3-phenyl-2-[3-(1H-pyrazol-4-yl)-phenyl]-propionitrile;-   2-[4-(3,5-dimethyl-1H-pyrazol-4-yl)-phenyl]-2-phenyl-ethylamine;-   2-(4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethylamine;-   2-[3-(3,5-dimethyl-1H-pyrazol-4-yl)-phenyl]-1-phenyl-ethylamine;-   3-phenyl-2-[3-(1H-pyrazol-4-yl)-phenyl]-propylamine;-   3-phenyl-2-[4-(1H-pyrazol-4-yl)-phenyl]-propylamine;-   {3-(4-chloro-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propyl}-methyl-amine;-   {3-(3,4-difluoro-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propyl}-methyl-amine;-   {3-(3-chloro-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propyl}-methyl-amine;-   3-(4-chloro-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propionamide;-   3-(4-chloro-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propylamine;-   3-(3,4-dichloro-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propylamine;-   4-(4-chloro-phenyl)-4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidine;-   4-(4-methoxy-phenyl)-4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidine;-   4-(4-chloro-phenyl)-1-methyl-4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidine;-   4-phenyl-4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidine;-   4-[4-(3,5-dimethyl-1H-pyrazol-4-yl)-phenyl]-4-phenyl-piperidine;-   dimethyl-{3-[4-(1H-pyrazol-4-yl)-phenyl]-3-pyridin-2-yl-propyl}-amine;-   {2-(4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-dimethyl-amine;-   {2-(4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-methyl-amine;-   {2-(4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-methyl-amine    (R);-   {2-(4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-methyl-amine    (S);-   4-{2-(4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-morpholine;-   4-{4-[1-(4-chloro-phenyl)-2-pyrrolidin-1-yl-ethyl]-phenyl}-1H-pyrazole;-   {2-(4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-isopropyl-amine;-   dimethyl-{2-phenyl-2-[4-(1H-pyrazol-4-yl)-phenyl]ethyl}-amine;-   {2,2-bis-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-dimethyl-amine;-   {2,2-bis-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-methyl-amine;-   2-(4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethylamine (R);-   2-(4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethylamine (S);-   2-(4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-acetamide;-   1-{2-(4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-piperazine;-   1-{2-(4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-piperidine;-   4-{4-[2-azetidin-1-yl-1-(4-chloro-phenyl)-ethyl]-phenyl}-1H-pyrazole;-   1-phenyl-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethylamine;-   2-(4-chloro-phenyl)-N-methyl-2-[4-(1H-pyrazol-4-yl)-phenyl]-acetamide;-   N-methyl-2,2-bis-[4-(1H-pyrazol-4-yl)-phenyl]-acetamide;-   {2-(4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}methyl-amine;    {2-(4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-ethyl-amine;-   4-{4-[1-(4-chloro-phenyl)-2-imidazol-1-yl-ethyl]-phenyl}-1H-pyrazole;-   methyl-{2-(4-phenoxy-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-amine;-   {2-(4-methoxy-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-methyl-amine;-   methyl-{2-[4-(pyrazin-2-yloxy)-phenyl]-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-amine;-   methyl-{2-phenoxy-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-amine;-   2-{(4-chloro-phenyl)-[4-(1H-pyrazol-4-yl)-phenyl]-methoxy}-ethylamine;-   4-{4-[1-(4-chloro-phenyl)-3-pyrrolidin-1-yl-propyl]-phenyl}-1H-pyrazole;-   4-{4-[3-azetidin-1-yl-1-(4-chloro-phenyl)-propyl]-phenyl}-1H-pyrazole;-   methyl-{3-naphthalen-2-yl-3-[4-(1H-pyrazol-4-yl)-phenyl]-propyl}-amine;-   dimethyl-(4-(3-methylamino-1-[4-(1H-pyrazol-4-yl)-phenyl]-propyl)-phenyl)-amine;-   {3-(4-fluoro-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propyl}-methyl-amine;-   4-{4-[4-(4-chloro-phenyl)-piperidin-4-yl]-phenyl}-1H-pyrazole-3-carbonitrile;-   3-(4-phenoxy-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propylamine;-   1-{(4-chloro-phenyl)-[4-(1H-pyrazol-4-yl)-phenyl]-methyl}-piperazine;-   1-methyl-4-{phenyl-[4-(1H-pyrazol-4-yl)-phenyl]-methyl}-[1,4]diazepane;-   {3-(3-chloro-phenoxy)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propyl}-methyl-amine;-   methyl-{2-phenyl-2-[6-(1H-pyrazol-4-yl)-pyridin-3-yl]-ethyl}-amine;-   4-{4-[1-(4-chloro-phenyl)-3-imidazol-1-yl-propyl]-phenyl}-1H-pyrazole;-   4-[4-(3-imidazol-1-yl-1-phenoxy-propyl)-phenyl]-1H-pyrazole;-   4-{4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidin-4-yl}-phenol;-   1-{(4-chloro-phenyl)-[4-(1H-pyrazol-4-yl)-phenyl]-methyl}-piperazine;-   {2-(4-fluoro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-methyl-amine;-   {2-(3-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-methyl-amine;-   4-[4-(2-methoxy-ethoxy)-phenyl]-4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidine;-   4-[4-(3-methoxy-propoxy)-phenyl]-4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidine;-   3-(3,4-dichloro-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propionamide;-   2-(4-{2-methylamino-1-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-phenoxy)-isonicotinamide;-   {2-(3-chloro-phenoxy)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-methyl-amine;-   3-{2-(4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethylamino}-propan-1-ol;-   2-{2-(4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethylamino}-ethanol;-   3-{2-(4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethylamino}-propan-1-ol;-   2-{2-(4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethylamino}-ethanol;-   {2-(4-Chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-cyclopropylmethyl-amine;-   methyl-[2-[4-(1H-pyrazol-4-yl)-phenyl]-2-(4-pyridin-3-yl-phenyl)-ethyl]-amine;-   4-{3-methylamino-1-[4-(1H-pyrazol-4-yl)-phenyl]-propyl}-phenol;-   3-(4-methoxy-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propylamine;-   4-(4-chloro-phenyl)-4-[4-(3-methyl-1H-pyrazol-4-yl)-phenyl]-piperidine;-   2-(4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-morpholine;-   (4-{4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidin-4-yl}-phenoxy)-acetic    acid;-   (4-{4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidin-4-yl}-phenoxy)-acetic    acid, methyl ester;-   4-{4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidin-4-yl}-benzonitrile;-   {2-(4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-propyl}-methyl-amine;-   1-(4-chloro-phenyl)-2-methylamino-1-[4-(1H-pyrazol-4-yl)-phenyl]-ethanol;-   2-amino-1-(4-chloro-phenyl)-1-[4-(1H-pyrazol-4-yl)-phenyl]-ethanol;-   4-(3,4-dichloro-phenyl)-4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidine;-   4-(3-chloro-4-methoxy-phenyl)-4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidine;-   4-(4-chloro-3-fluoro-phenyl)-4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidine;-   4-{4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidin-4-yl}-benzoic acid;-   4-[4-(1H-pyrazol-4-yl)-phenyl]-1,2,3,4,5,6-hexahydro-[4,4′]bipyridinyl;-   3-(3-chloro-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propylamine;-   2-methylamino-1-(4-nitro-phenyl)-1-[4-(1H-pyrazol-4-yl)-phenyl]-ethanol;-   2-(3-chloro-4-methoxy-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethylamine;-   2-(4-chloro-phenyl)-2-fluoro-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethylamine;-   3-(3,4-dichloro-phenyl)-3-[6-(1H-pyrazol-4-yl)-pyridin-3-yl]-propylamine;-   2-(4-chloro-3-fluoro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethylamine;-   4-(2-chloro-3-fluoro-phenyl)-4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidine;-   1-{(3,4-dichloro-phenyl)-[4-(1H-pyrazol-4-yl)-phenyl]-methyl}-piperazine;-   2-(3,4-dichloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethylamine;-   {2-(3-chloro-4-methoxy-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-methyl-amine;-   4-{4-[2-azetidin-1-yl-1-(4-chloro-phenoxy)-ethyl]-phenyl}-1H-pyrazole;-   3-(3-chloro-4-methoxy-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propylamine;-   {3-(3-chloro-4-methoxy-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propyl}-methyl-amine;-   1-{(3,4-dichloro-phenyl)-[4-(1H-pyrazol-4-yl)-phenyl]-methyl}-piperazine;    and-   C-(4-chloro-phenyl)-C-[4-(1H-pyrazol-4-yl)-phenyl]-methylamine;

and salts, solvates, tautomers and N-oxides thereof.

In one embodiment, the compound of the formula (I) is selected from thegroup consisting of:

-   {2-(4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-methyl-amine    (R);-   4-(4-chloro-phenyl)-4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidine;-   3-(4-chloro-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propylamine;-   3-(3,4-dichloro-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propylamine;-   {3-(4-chloro-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propyl}-methyl-amine;-   {2-(4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-dimethyl-amine;    and-   2-(4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethylamine.

A further subset of compounds of the formula (I) consists of

-   4-(3-chloro-4-methoxy-phenyl)-4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidine;-   2-(4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethylamine (R    isomer);

and salts, solvates, tautomers and N-oxides thereof.

Salts, Solvates, Tautomers, Isomers, N-Oxides, Esters, Prodrugs andIsotopes

In this section, as in all other sections of this application, unlessthe context indicates otherwise, references to formula (I) includedreferences to formulae (Ia), (Ib), (II), (III), (IV) and (V) and allother sub-groups, preferences and examples thereof as defined herein.

Unless otherwise specified, a reference to a particular compound(including inter alia any of the compounds of formula (I) or theancillary compounds described herein) also includes ionic, salt,solvate, and protected forms thereof, for example, as discussed below.

Many compounds (including those of the formula (I) and many of theancillary compounds described herein) can exist in the form of salts,for example acid addition salts or, in certain cases salts of organicand inorganic bases such as carboxylate, sulphonate and phosphate salts.All such salts are within the scope of this invention, and references tocompounds (e.g. compounds of the formula (I) or ancillary compounds)include the salt forms of the compounds. As in the preceding sections ofthis application, all references to formula (I) should be taken to referalso to formula (II) and sub-groups thereof unless the context indicatesotherwise.

Salt forms may be selected and prepared according to methods describedin Pharmaceutical Salts: Properties, Selection, and Use, P. HeinrichStahl (Editor), Camille G. Wermuth (Editor), ISBN: 3-90639-026-8,Hardcover, 388 pages, August 2002. For example, acid addition salts maybe prepared by dissolving the free base in an organic solvent in which agiven salt form is insoluble or poorly soluble and then adding therequired acid in an appropriate solvent so that the salt precipitatesout of solution.

Acid addition salts may be formed with a wide variety of acids, bothinorganic and organic. Examples of acid addition salts include saltsformed with an acid selected from the group consisting of acetic,2,2-dichloroacetic, adipic, alginic, ascorbic (e.g. L-ascorbic),L-aspartic, benzenesulphonic, benzoic, 4-acetamidobenzoic, butanoic, (+)camphoric, camphor-sulphonic, (+)-(1S)-camphor-10-sulphonic, capric,caproic, caprylic, cinnamic, citric, cyclamic, dodecylsulphuric,ethane-1,2-disulphonic, ethanesulphonic, 2-hydroxyethanesulphonic,formic, fumaric, galactaric, gentisic, glucoheptonic, D-gluconic,glucuronic (e.g. D-glucuronic), glutamic (e.g. L-glutamic),α-oxoglutaric, glycolic, hippuric, hydrobromic, hydrochloric, hydriodic,isethionic, lactic (e.g. (+)-L-lactic and (±)-DL-lactic), lactobionic,maleic, malic, (−)-L-malic, malonic, (±)-DL-mandelic, methanesulphonic,naphthalenesulphonic (e.g. naphthalene-2-sulphonic),naphthalene-1,5-disulphonic, 1-hydroxy-2-naphthoic, nicotinic, nitric,oleic, orotic, oxalic, palmitic, pamoic, phosphoric, propionic,L-pyroglutamic, salicylic, 4-amino-salicylic, sebacic, stearic,succinic, sulphuric, tannic, (+)-L-tartaric, thiocyanic,toluenesulphonic (e.g. p-toluenesulphonic), undecylenic and valericacids, as well as acylated amino acids and cation exchange resins.

One particular group of acid addition salts includes salts formed withhydrochloric, hydriodic, phosphoric, nitric, sulphuric, citric, lactic,succinic, maleic, malic, isethionic, fumaric, benzenesulphonic,toluenesulphonic, methanesulphonic, ethanesulphonic,naphthalenesulphonic, valeric, acetic, propanoic, butanoic, malonic,glucuronic and lactobionic acids.

Another group of acid addition salts includes salts formed from acetic,adipic, ascorbic, aspartic, citric, DL-Lactic, fumaric, gluconic,glucuronic, hippuric, hydrochloric, glutamic, DL-malic,methanesulphonic, sebacic, stearic, succinic and tartaric acids.

The compounds comprised in the combinations of the invention may existas mono- or di-salts depending upon the pKa of the acid from which thesalt is formed. In stronger acids, the basic pyrazole nitrogen, as wellas the nitrogen atom in the group NR²R³, may take part in saltformation. For example, where the acid has a pKa of less than about 3(e.g. an acid such as hydrochloric acid, sulphuric acid ortrifluoroacetic acid), the compounds will typically form salts with 2molar equivalents of the acid.

If the compound is anionic, or has a functional group which may beanionic (e.g., —COOH may be —COO⁻), then a salt may be formed with asuitable cation. Examples of suitable inorganic cations include, but arenot limited to, alkali metal ions such as Na⁺ and K⁺, alkaline earthcations such as Ca²⁺ and Mg²⁺, and other cations such as Al³⁺. Examplesof suitable organic cations include, but are not limited to, ammoniumion (i.e., NH₄ ⁺) and substituted ammonium ions (e.g., NH₃R⁺, NH₂R₂ ⁺,NHR₃ ⁺, NR₄ ⁺). Examples of some suitable substituted ammonium ions arethose derived from: ethylamine, diethylamine, dicyclohexylamine,triethylamine, butylamine, ethylenediamine, ethanolamine,diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline,meglumine, and tromethamine, as well as amino acids, such as lysine andarginine. An example of a common quaternary ammonium ion is N(CH₃)₄ ⁺.

Where the compounds contain an amine function, these may form quaternaryammonium salts, for example by reaction with an alkylating agentaccording to methods well known to the skilled person. Such quaternaryammonium compounds are within the scope of formula (I).

Compounds containing an amine function may also form N-oxides. Areference herein to a compound (e.g. a compound of the formula (I)) thatcontains an amine function also includes the N-oxide.

Where a compound contains several amine functions, one or more than onenitrogen atom may be oxidised to form an N-oxide. Particular examples ofN-oxides are the N-oxides of a tertiary amine or a nitrogen atom of anitrogen-containing heterocycle.

N-Oxides can be formed by treatment of the corresponding amine with anoxidizing agent such as hydrogen peroxide or a per-acid (e.g. aperoxycarboxylic acid), see for example Advanced Organic Chemistry, byJerry March, 4^(th) Edition, Wiley Interscience, pages. Moreparticularly, N-oxides can be made by the procedure of L. W. Deady (Syn.Comm. 1977, 7, 509-514) in which the amine compound is reacted withm-chloroperoxybenzoic acid (MCPBA), for example, in an inert solventsuch as dichloromethane.

The compounds of the combinations of the invention (for example, thecompounds of formula (I)) may exist in a number of different geometricisomeric, and tautomeric forms and references to such compounds includeall such forms. For the avoidance of doubt, where a compound can existin one of several geometric isomeric or tautomeric forms and only one isspecifically described or shown, all others are nevertheless embraced(particularly in the case of formula (I)).

For example, in compounds of the formula (I) the pyrazole group may takeeither of the following two tautomeric forms A and B.

For simplicity, the general formula (I) illustrates form A but theformula is to be taken as embracing both form A and form B.

Where any constituent compound of the combination of the invention (e.g.of the formula (I)) contain one or more chiral centres, and can exist inthe form of two or more optical isomers, references to the compoundsinclude all optical isomeric forms thereof (e.g. enantiomers anddiastereoisomers), either as individual optical isomers, or mixtures ortwo or more optical isomers, unless the context requires otherwise.

For example, the group A can include one or more chiral centres. Thus,when E and are both attached to the same carbon atom on the linker groupA, the said carbon atom is typically chiral and hence the compound ofthe formula (I) will exist as a pair of enantiomers (or more than onepair of enantiomers where more than one chiral centre is present in thecompound).

The optical isomers may be characterised and identified by their opticalactivity (i.e. as + and − isomers) or they may be characterised in termsof their absolute stereochemistry using the “R and S” nomenclaturedeveloped by Cahn, Ingold and Prelog, see Advanced Organic Chemistry byJerry March, 4^(th) Edition, John Wiley & Sons, New York, 1992, pages109-114, and see also Cahn, Ingold & Prelog, Angew. Chem. Int. Ed.Engl., 1966, 5, 385-415.

Optical isomers can be separated by a number of techniques includingchiral chromatography (chromatography on a chiral support) and suchtechniques are well known to the person skilled in the art.

As an alternative to chiral chromatography, optical isomers can beseparated by forming diastereoisomeric salts with chiral acids such as(+)-tartaric acid, (−)-pyroglutamic acid, (−)-di-toluloyl-L-tartaricacid, (+)-mandelic acid, (−)-malic acid, and (−)-camphorsulphonic,separating the diastereoisomers by preferential crystallisation, andthen dissociating the salts to give the individual enantiomer of thefree base.

Where any one constituent compound of the combinations of the invention(e.g. a compound of the formula (I)) exist as two or more opticalisomeric forms, one enantiomer in a pair of enantiomers may exhibitadvantages over the other enantiomer, for example, in terms ofbiological activity. Thus, in certain circumstances, it may be desirableto use as a component in the combination of the invention only one of apair of enantiomers, or only one of a plurality of diastereoisomers.Accordingly, the invention provides combinations containing a compoundof the formula (I) having one or more chiral centres, wherein at least55% (e.g. at least 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95%) of thecompound of the formula (I) is present as a single optical isomer (e.g.enantiomer or diastereoisomer). In one general embodiment, 99% or more(e.g. substantially all) of the total amount of the compound of theformula (I) may be present as a single optical isomer (e.g. enantiomeror diastereoisomer).

Esters such as carboxylic acid esters and acyloxy esters of thecompounds (e.g. of formula (I)) bearing a carboxylic acid group or ahydroxyl group are also contemplated (and in the case of compounds offormula (I) intended to be embraced by that formula). In one embodimentof the invention, formula (I) includes within its scope esters ofcompounds of the formula (I) bearing a carboxylic acid group or ahydroxyl group. In another embodiment of the invention, formula (I) doesnot include within its scope esters of compounds of the formula (I)bearing a carboxylic acid group or a hydroxyl group. Examples of estersare compounds containing the group —C(═O)OR, wherein R is an estersubstituent, for example, a C₁₋₇ alkyl group, a C₃₋₂₀ heterocyclylgroup, or a C₅₋₂₀ aryl group, preferably a C₁₋₇ alkyl group. Particularexamples of ester groups include, but are not limited to, —C(═O)OCH₃,—C(═O)OCH₂CH₃, —C(═O)OC(CH₃)₃, and —C(═O)OPh. Examples of acyloxy(reverse ester) groups are represented by —OC(═O)R, wherein R is anacyloxy substituent, for example, a C₁₋₇ alkyl group, aC₃₋₂₀heterocyclyl group, or a C₅₋₂₀ aryl group, preferably a C₁₋₇ alkylgroup. Particular examples of acyloxy groups include, but are notlimited to, —OC(═O)CH₃ (acetoxy), —OC(═O)CH₂CH₃, —OC(═O)C(CH₃)₃,—OC(═O)Ph, and —OC(═O)CH₂Ph.

Also contemplated are any polymorphic forms of the compounds, solvates(e.g. hydrates), complexes (e.g. inclusion complexes or clathrates withcompounds such as cyclodextrins, or complexes with metals) of theconstituent compounds of the combinations of the invention (and ofFormula (I) in particular), and pro-drugs of these constituentcompounds. By “prodrugs” is meant for example any compound that isconverted in vivo into a biologically active compound (e.g. into anancillary compound or into a compound of the formula (I)).

For example, some prodrugs are esters of the active compound (e.g., aphysiologically acceptable metabolically labile ester). Duringmetabolism, the ester group (—C(═O)OR) is cleaved to yield the activedrug. Such esters may be formed by esterification, for example, of anyof the carboxylic acid groups (—C(═O)OH) in the parent compound, with,where appropriate, prior protection of any other reactive groups presentin the parent compound, followed by deprotection if required.

Examples of such metabolically labile esters include those of theformula —C(═O)OR wherein R is:

C₁₋₇alkyl (e.g., -Me, -Et, -nPr, -iPr, -nBu, -sBu, -iBu, -tBu);

C₁₋₇ aminoalkyl (e.g., aminoethyl; 2-(N,N-diethylamino)ethyl;2-(4-morpholino)ethyl); and acyloxy-C₁₋₄alkyl (e.g., acyloxymethyl;acyloxyethyl; pivaloyloxymethyl; acetoxymethyl; 1-acetoxyethyl;1-(1-methoxy-1-methyl)ethyl-carbonyloxyethyl; 1-(benzoyloxy)ethyl;isopropoxy-carbonyloxymethyl; 1-isopropoxy-carbonyloxyethyl;cyclohexyl-carbonyloxymethyl; 1-cyclohexyl-carbonyloxyethyl;cyclohexyloxy-carbonyloxymethyl; 1-cyclohexyloxy-carbonyloxyethyl;(4-tetrahydropyranyloxy)carbonyloxymethyl;1-(4-tetrahydropyranyloxy)-carbonyloxyethyl;(4-tetrahydropyranyl)carbonyloxymethyl; and1-(4-tetrahydropyranyl)-carbonyloxyethyl).

Also, some prodrugs are activated enzymatically to yield the activecompound, or a compound which, upon further chemical reaction, yieldsthe active compound (for example, as in antigen-directed enzyme pro-drugtherapy (ADEPT), gene-directed enzyme pro-drug therapy (GDEPT) andligand-directed enzyme pro-drug therapy (LIDEPT). For example, theprodrug may be a sugar derivative or other glycoside conjugate, or maybe an amino acid ester derivative.

As used herein, the term “combination”, as applied to two or morecompounds, is intended to define material in which the two or morecompounds are associated. The terms “combined” and “combining” in thiscontext are to be interpreted accordingly.

The association of the two or more compounds in a combination may bephysical or non-physical. Examples of physically associated combinedcompounds include:

-   -   compositions (e.g. unitary formulations) comprising the two or        more compounds in admixture (for example within the same unit        dose);    -   compositions comprising material in which the two or more        compounds are chemically/physicochemically linked (for example        by crosslinking, molecular agglomeration or binding to a common        vehicle moiety);    -   compositions comprising material in which the two or more        compounds are chemically/physicochemically co-packaged (for        example, disposed on or within lipid vesicles, particles (e.g.        micro- or nanoparticles) or emulsion droplets);    -   pharmaceutical kits, pharmaceutical packs or patient packs in        which the two or more compounds are co-packaged or co-presented        (e.g. as part of an array of unit doses);

Examples of non-physically associated combined compounds include:

-   -   material (e.g. a non-unitary formulation) comprising at least        one of the two or more compounds together with instructions for        the extemporaneous association of the at least one compound to        form a physical association of the two or more compounds;    -   material (e.g. a non-unitary formulation) comprising at least        one of the two or more compounds together with instructions for        combination therapy with the two or more compounds;    -   material comprising at least one of the two or more compounds        together with instructions for administration to a patient        population in which the other(s) of the two or more compounds        have been (or are being) administered;    -   material comprising at least one of the two or more compounds in        an amount or in a form which is specifically adapted for use in        combination with the other(s) of the two or more compounds.

As used herein, the term “combination therapy” is intended to definetherapies which comprise the use of a combination of two or morecompounds (as defined above). Thus, references to “combination therapy”,“combinations” and the use of compounds “in combination” in thisapplication may refer to compounds that are administered as part of thesame overall treatment regimen. As such, the posology of each of the twoor more compounds may differ: each may be administered at the same timeor at different times. It will therefore be appreciated that thecompounds of the combination may be administered sequentially (e.g.before or after) or simultaneously, either in the same pharmaceuticalformulation (i.e. together), or in different pharmaceutical formulations(i.e. separately). Simultaneously in the same formulation is as aunitary formulation whereas simultaneously in different pharmaceuticalformulations is non-unitary. The posologies of each of the two or morecompounds in a combination therapy may also differ with respect to theroute of administration.

As used herein, the term “pharmaceutical kit” defines an array of one ormore unit doses of a pharmaceutical composition together with dosingmeans (e.g. measuring device) and/or delivery means (e.g. inhaler orsyringe), optionally all contained within common outer packaging. Inpharmaceutical kits comprising a combination of two or more compounds,the individual compounds may unitary or non-unitary formulations. Theunit dose(s) may be contained within a blister pack. The pharmaceuticalkit may optionally further comprise instructions for use.

As used herein, the term “pharmaceutical pack” defines an array of oneor more unit doses of a pharmaceutical composition, optionally containedwithin common outer packaging. In pharmaceutical packs comprising acombination of two or more compounds, the individual compounds mayunitary or non-unitary formulations. The unit dose(s) may be containedwithin a blister pack. The pharmaceutical pack may optionally furthercomprise instructions for use.

As used herein, the term “patient pack” defines a package, prescribed toa patient, which contains pharmaceutical compositions for the wholecourse of treatment. Patient packs usually contain one or more blisterpack(s). Patient packs have an advantage over traditional prescriptions,where a pharmacist divides a patient's supply of a pharmaceutical from abulk supply, in that the patient always has access to the package insertcontained in the patient pack, normally missing in patientprescriptions. The inclusion of a package insert has been shown toimprove patient compliance with the physician's instructions.

The combinations of the invention may produce a therapeuticallyefficacious effect relative to the therapeutic effect of the individualcompounds when administered separately.

The term ‘efficacious’ includes advantageous effects such as additivity,synergism, reduced side effects, reduced toxicity, increased time todisease progression, increased time of survival, sensitization orresensitization of one agent to another, or improved response rate.Advantageously, an efficacious effect may allow for lower doses of eachor either component to be administered to a patient, thereby decreasingthe toxicity of chemotherapy, whilst producing and/or maintaining thesame therapeutic effect. Efficacious combinations may be determined, forexample, by the methods described herein (see Example 109, below).

A “synergistic” effect in the present context refers to a therapeuticeffect produced by the combination which is larger than the sum of thetherapeutic effects of the components of the combination when presentedindividually.

An “additive” effect in the present context refers to a therapeuticeffect produced by the combination which is larger than the therapeuticeffect of any of the components of the combination when presentedindividually.

The term “response rate” as used herein refers, in the case of a solidtumour, to the extent of reduction in the size of the tumour at a giventime point, for example 12 weeks. Thus, for example, a 50% response ratemeans a reduction in tumour size of 50%. References herein to a“clinical response” refer to response rates of 50% or greater. A“partial response” is defined herein as being a response rate of lessthan 50%.

The term “ancillary compound” as used herein is intended to define anycompound which yields an efficacious combination (as herein defined)when combined with a compound of the formula (I). The ancillary compoundmay therefore act as an adjunct to the compound of formula (I), or mayotherwise contribute to the efficacy of the combination (for example, byproducing a synergistic or additive effect or improving the responserate, as herein defined). In embodiments where the combinations comprisetwo or more ancillary compounds, each of the two ancillary compounds maybe independently efficacious, or they may yield efficacious combinationswhen each of the two or more compounds are combined with the compound offormula I.

Methods for the Preparation of Compounds of the Formula (I)

In this section, as in all other sections of this application, unlessthe context indicates otherwise, references to formula (I) includedreferences to formulae (Ia), (Ib), (II), (III), (IV) and (V) and allother sub-groups, preferences and examples thereof as defined herein.

Compounds of the formula (I) can be prepared by reaction of a compoundof the formula (X) with a compound of the formula (XI) or an N-protectedderivative thereof:

wherein A, E, and R¹ to R⁵ are as hereinbefore defined, one of thegroups X and Y is chlorine, bromine or iodine or atrifluoromethanesulphonate (triflate) group, and the other one of thegroups X and Y is a boronate residue, for example a boronate ester orboronic acid residue.

The reaction can be carried out under typical Suzuki Coupling conditionsin the presence of a palladium catalyst such asbis(tri-t-butylphosphine)palladium and a base (e.g. a carbonate such aspotassium carbonate). The reaction may be carried out in an aqueoussolvent system, for example aqueous ethanol, and the reaction mixture istypically subjected to heating, for example to a temperature in excessof 100° C.

An illustrative synthetic route involving a Suzuki coupling step isshown in Scheme 1. The starting material for the synthetic route shownin scheme 1 is the halo-substituted aryl- or heteroarylmethyl nitrile(XII) in which X is a chlorine, bromine or iodine atom or a triflategroup. The nitrile (XII) is condensed with the aldehyde R¹CHO in thepresence of an alkali such as sodium or potassium hydroxide in anaqueous solvent system such as aqueous ethanol. The reaction can becarried out at room temperature.

The resulting substituted acrylonitrile derivative (XIII) is thentreated with a reducing agent that will selectively reduce the alkenedouble bond without reducing the nitrile group. A borohydride such assodium borohydride may be used for this purpose to give the substitutedacetonitrile derivative (XIV). The reduction reaction is typicallycarried out in a solvent such as ethanol and usually with heating, forexample to a temperature up to about 65° C.

The reduced nitrile (XIV) is then coupled with the pyrazole boronateester (XV) under the Suzuki coupling conditions described above to givea compound of the formula (I) in which A-NR²R³ is a substitutedacetonitrile group.

The substituted acetonitrile compound (XVI) may then be reduced to thecorresponding amine (XVII) by treatment with a suitable reducing agentsuch as Raney nickel and ammonia in ethanol.

The synthetic route shown in Scheme 1 gives use to amino compounds ofthe formula (I) in which the aryl or heteroaryl group E is attached tothe S-position of the group A relative to the amino group. In order togive amino compounds of the formula (I) in which R¹ is attached to theβ-position relative to the amino group, the functional groups on the twostarting materials in the condensation step can be reversed so that acompound of the formula X-E-CHO wherein X is bromine, chlorine, iodineor a triflate group is condensed with a compound of the formulaR¹—CH₂—CN to give a substituted acrylonitrile derivative which is thenreduced to the corresponding acetonitrile derivative before couplingwith the pyrazole boronate (XV) and reducing the cyano group to an aminogroup.

Compounds of the formula (I) in which R¹ is attached to the α-positionrelative to the amino group can be prepared by the sequence of reactionsshown in Scheme 2.

In Scheme 2, the starting material is a halo-substituted aryl- orheteroarylmethyl Grignard reagent (XVIII, X=bromine or chlorine) whichis reacted with the nitrile R¹—CN in a dry ether such as diethyl etherto give an intermediate imine (not shown) which is reduced to give theamine (XIX) using a reducing agent such as lithium aluminium hydride.The amine (XIX) can be reacted with the boronate ester (XV) under theSuzuki coupling conditions described above to yield the amine (XX).

Compounds of the formula (I) can also be prepared from the substitutednitrile compound (XXI):

wherein PG is a protecting group such as a tetrahydropyranyl group. Thenitrile (XXI) can be condensed with an aldehyde of the formulaR¹—(CH₂)_(r)—CHO, wherein r is 0 or 1, and the resulting substitutedacrylonitrile subsequently reduced to the corresponding substitutednitrile under conditions analogous to those set out in Scheme 1 above.The protecting group PG can then be removed by an appropriate method.The nitrile compound may subsequently be reduced to the correspondingamine by the use of a suitable reducing agent as described above.

The nitrile compound (XXI) may also be reacted with a Grignard reagentof the formula R¹—(CH₂)_(r)—MgBr under standard Grignard reactionconditions followed by deprotection to give an amino compound of theinvention which has the structure shown in formula (XXII).

In the preparative procedures outlined above, the coupling of the arylor heteroaryl group E to the pyrazole is accomplished by reacting ahalo-pyrazole or halo-aryl or heteroaryl compound with a boronate esteror boronic acid in the presence of a palladium catalyst and base. Manyboronates suitable for use in preparing compounds of the invention arecommercially available, for example from Boron Molecular Limited ofNoble Park, Australia, or from Combi-Blocks Inc, of San Diego, USA.Where the boronates are not commercially available, they can be preparedby methods known in the art, for example as described in the reviewarticle by N. Miyaura and A. Suzuki, Chem. Rev. 1995, 95, 2457. Thus,boronates can be prepared by reacting the corresponding bromo-compoundwith an alkyl lithium such as butyl lithium and then reacting with aborate ester. The resulting boronate ester derivative can, if desired,be hydrolysed to give the corresponding boronic acid.

Compounds of the formula (I) in which the group A contains a nitrogenatom attached to the group E can be prepared by well known syntheticprocedures from compounds of the formula (XXIII) or a protected formthereof. Compounds of the formula (XXIII) can be obtained by a Suzukicoupling reaction of a compound of the formula (XV) (see Scheme 1) witha compound of the formula Br-E-NH₂ such as 4-bromoaniline.

Compounds of the formula (I) in which R¹ and E are connected to the samecarbon atom can be prepared as shown in Scheme 3.

In Scheme 3, an aldehyde compound (XXIV) where X is bromine, chlorine,iodine or a triflate group is condensed with ethyl cyanoacetate in thepresence of a base to give a cyanoacrylate ester intermediate (XXV). Thecondensation is typically carried out in the presence of a base,preferably a non-hydroxide such as piperidine, by heating under DeanStark conditions.

The cyanoacrylate intermediate (XXV) is then reacted with a Grignardreagent R¹MgBr suitable for introducing the group R¹ by Michael additionto the carbon-carbon double bond of the acrylate moiety. The Grignardreaction may be carried out in a polar non-protic solvent such astetrahydrofuran at a low temperature, for example at around 0° C. Theproduct of the Grignard reaction is the cyano propionic acid ester(XXVI) and this is subjected to hydrolysis and decarboxylation to givethe propionic acid derivative (XXVII). The hydrolysis anddecarboxylation steps can be effected by heating in an acidic medium,for example a mixture of sulphuric acid and acetic acid.

The propionic acid derivative (XXVII) is converted to the amide (XXVIII)by reaction with an amine HNR²R³ under conditions suitable for formingan amide bond. The coupling reaction between the propionic acidderivative (XXVII) and the amine HNR²R³ is preferably carried out in thepresence of a reagent of the type commonly used in the formation ofpeptide linkages. Examples of such reagents include1,3-dicyclohexylcarbodiimide (DCC) (Sheehan et al, J. Amer. Chem Soc.1955, 77, 1067), 1-ethyl-3-(3′-dimethylaminopropyl)-carbodiimide(referred to herein either as EDC or EDAC) (Sheehan of al, J. Org.Chem., 1961, 26, 2525), uronium-based coupling agents such asO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU) and phosphonium-based coupling agents such as1-benzo-triazolyloxytris-(pyrrolidino)phosphonium hexafluorophosphate(PyBOP) (Castro et al, Tetrahedron Letters, 1990, 31, 205).Carbodiimide-based coupling agents are advantageously used incombination with 1-hydroxy-7-azabenzotriazole (HOAt) (L. A. Carpino, J.Amer. Chem. Soc., 1993, 115, 4397) or 1-hydroxybenzotriazole (HOBt)(Konig et al, Chem. Ber., 103, 708, 2024-2034). Preferred couplingreagents include EDC (EDAC) and DCC in combination with HOAt or HOBt.

The coupling reaction is typically carried out in a non-aqueous,non-protic solvent such as acetonitrile, dioxan, dimethylsulphoxide,dichloromethane, dimethylformamide or N-methylpyrrolidine, or in anaqueous solvent optionally together with one or more miscibleco-solvents. The reaction can be carried out at room temperature or,where the reactants are less reactive (for example in the case ofelectron-poor anilines bearing electron withdrawing groups such assulphonamide groups) at an appropriately elevated temperature. Thereaction may be carried out in the presence of a non-interfering base,for example a tertiary amine such as triethylamine orN,N-diisopropylethylamine.

Where the amine HNR²R³ is ammonia, the amide coupling reaction can becarried out using 1,1′-carbonyldiimidazole (CDI) to activate thecarboxylic acid before addition of the ammonia.

As an alternative, a reactive derivative of the carboxylic acid, e.g. ananhydride or acid chloride, may be used. Reaction with a reactivederivative such an anhydride is typically accomplished by stirring theamine and anhydride at room temperature in the presence of a base suchas pyridine.

The amide (XXVIII) can be converted to a compound of the formula (XXX)(which corresponds to a compound of the formula (I) wherein A has an oxosubstituent next to the NR²R³ group) by reaction with a boronate (XV)under Suzuki coupling conditions as described above. The amide (XXX) cansubsequently be reduced using a hydride reducing agent such as lithiumaluminium hydride in the presence of aluminium chloride to give an amineof the formula (XXXI) (which corresponds to a compound of the formula(I) wherein A is CH—CH₂—CH₂—). The reduction reaction is typicallycarried out in an ether solvent, for example diethyl ether, with heatingto the reflux temperature of the solvent.

Rather than reacting the amide (XXVIII) with the boronate (XV), theamide may instead be reduced with lithium aluminium hydride/aluminiumchloride, for example in an ether solvent at ambient temperature, togive the amine (XXIX) which is then reacted with the boronate (XV) underthe Suzuki coupling conditions described above to give the amine (XXX).

In order to obtain the homologue of the amine (XXIX) containing onefewer methylene group, the carboxylic acid (XXVII) can be converted tothe azide by standard methods and subjected to a Curtius rearrangementin the presence of an alcohol such as benzyl alcohol to give a carbamate(see Advanced Organic Chemistry, 4^(th) edition, by Jerry March, JohnWiley & sons, 1992, pages 1091-1092). The benzylcarbamate can functionas a protecting group for the amine during the subsequent Suzukicoupling step, and the benzyloxycarbonyl moiety in the carbamate groupcan then be removed by standard methods after the coupling step.Alternatively, the benzylcarbamate group can be treated with a hydridereducing agent such as lithium aluminium hydride to give a compound inwhich NR²R³ is a methylamino group instead of an amino group.

Intermediate compounds of the formula (X) where the moiety X is achlorine, bromine or iodine atom and A is a group CH—CH₂— can beprepared by the reductive amination of an aldehyde compound of theformula (XXXII):

with an amine of the formula HNR²R³ under standard reductive aminationconditions, for example in the presence of sodium cyanoborohydride in analcohol solvent such as methanol or ethanol.

The aldehyde compound (XXXII) can be obtained by oxidation of thecorresponding alcohol (XXXIII) using, for example, the Dess-Martinperiodinane (see Dess, D. B.; Martin, J. C. J. Org. Soc., 1983, 48, 4155and Organic Syntheses, Vol. 77, 141).

Compounds of the formula (I) where A, N and R² together form a cyclicgroup can be formed by the Suzuki coupling of a boronate compound of theformula (XV) with a cyclic intermediate of the formula (XXXIV) or anN-protected derivative thereof.

Cyclic intermediates of the formula (XXXIV), where R¹ is an aryl groupsuch as an optionally substituted phenyl group, can be formed by FriedelCrafts alkylation of an aryl compound R¹—H with a compound of theformula (XXXV):

The alkylation is typically carried out in the presence of a Lewis acidsuch as aluminium chloride at a reduced temperature, for example lessthan 5° C.

The Friedel Crafts reaction has been found to be of generalapplicability to the preparation of a range of intermediates of theformula (X). Accordingly, in a general method of making compounds of theformula (X), a compound of the formula (LXX):

is reacted with a compound of the formula R¹—H under Friedel Craftsalkylation conditions, for example in the presence of an aluminium,halide (e.g. AlCl₃).

In a further method for the preparation of a compound of the formula (I)wherein the moiety NR²R³ is attached to a CH₂ group of the moiety A, analdehyde of the formula (XXXVI) can be coupled with an amine of theformula HNR²R³ under reductive amination conditions as described above.In the formulae (XXXVI) and (XXXVII), A′ is the residue of the groupA—i.e. the moieties A′ and CH₂ together form the group A. The aldehyde(XXXVII) can be formed by oxidation of the corresponding alcohol using,for example, Dess-Martin periodinane.

A Friedel Crafts alkylation procedure of the type described above forthe synthesis of intermediates of the formula (XXXIV) can also be usedto prepare intermediates of the formula (X) wherein X is bromine. Anexample of such a procedure is shown in Scheme 4.

The starting material for the synthetic route shown in Scheme 4 is theepoxide (XXXVIII) which can either be obtained commercially or can bemade by methods well known to the skilled person, for example byreaction of the aldehyde Br-E-CHO with trimethylsulphonium iodide. Theepoxide (XXXVIII) is reacted with an amine HNR²R³ under conditionssuitable for a ring-opening reaction with the epoxide to give a compoundof the formula (XXXIX). The ring opening reaction can be carried out ina polar solvent such as ethanol at room temperature or optionally withmild heating, and typically with a large excess of the amine.

The amine (XXXIX) is then reacted with an aryl compound R¹H, typically aphenyl compound, capable of taking part in a Friedel Crafts alkylation(see for example Advanced Organic Chemistry, by Jerry March, pages534-542). Thus, the amine of formula (XXXIX) is typically reacted withthe aryl compound R¹H in the presence of an aluminium chloride catalystat or around room temperature. Where the aryl compound R¹H is a liquid,e.g. as in the case of a methoxybenzene (e.g. anisole) or a halobenzenesuch as chlorobenzene, the aryl compound may serve as the solvent.Otherwise, a less reactive solvent such as nitrobenzene may be used. TheFriedel Crafts alkylation of the compound R¹H with the amine (XXXIX)gives a compound of the formula (XL) which corresponds to a compound ofthe formula (X) wherein X is bromine and A is CHCH₂.

The hydroxy intermediate (XXXIX) in Scheme 4 can also be used to preparecompounds of the formula (X) in which the carbon atom of the hydrocarbonlinker group A adjacent the group R¹ is replaced by an oxygen atom. Thusthe compound of formula (XXXIX), or an N-protected derivative thereof(where R² or R³ are hydrogen) can be reacted with a phenolic compound ofthe formula R¹—OH under Mitsunobu alkylation conditions, e.g. in thepresence of diethyl azodicarboxylate and triphenylphosphine. Thereaction is typically carried out in a polar non-protic solvent such astetrahydrofuran at a moderate temperature such as ambient temperature.

A further use of the hydroxy-intermediate (XXXIX) is for the preparationof the corresponding fluoro-compound. Thus, the hydroxy group can bereplaced by fluorine by reaction with pyridine:hydrogen fluoride complex(Olah's reagent). The fluorinated intermediate can then be subjected toa Suzuki coupling reaction to give a compound of the formula (I) with afluorinated hydrocarbon group A. A fluorinated compound of the formula(I) could alternatively be prepared by first coupling the hydroxyintermediate (XXXIX), or a protected form thereof, with a pyrazoleboronic acid or boronate under Suzuki conditions and then replacing thehydroxy group in the resulting compound of formula (I) with fluorineusing pyridine:hydrogen fluoride complex.

Compounds of the formula (I) in which the moiety:

is a group:

where A″ is the hydrocarbon residue of the group A, can be prepared bythe sequence of reactions shown in Scheme 5.

As shown in Scheme 5, the aldehyde (XXIV) is reacted with a Grignardreagent R¹MgBr under standard Grignard conditions to give the secondaryalcohol (XLI). The secondary alcohol can then be reacted with a compoundof the formula (XLII) in which R^(2′) and R^(3′) represent the groups R²and R³ or an amine-protecting group, A″ is the residue of the group A,and X′ represents a hydroxy group or a leaving group.

The amine protecting group can be, for example, a phthalolyl group inwhich case NR^(2′)R^(3′) is a phthalimido group.

When X′ is a hydroxy group, the reaction between compound (XLI) and(XLII) can take the form of an toluene sulphonic acid catalysedcondensation reaction. Alternatively, when X′ is a leaving group such ashalogen, the alcohol (XLI) can first be treated with a strong base suchas sodium hydride to form the alcoholate which then reacts with thecompound (XLII).

The resulting compound of the formula (XLIII) is then subjected to aSuzuki coupling reaction with the pyrazole boronate reagent (XV) undertypical Suzuki coupling conditions of the type described above to give acompound of the formula (XLIV). The protecting group can then be removedfrom the protected amine group NR^(2′)R^(3′) to give a compound of theformula (I).

Compounds of the formula (I) in which the moiety:

is a group:

where A″ is the hydrocarbon residue of the group A, can be prepared bythe sequence of reactions shown in Scheme 6.

The starting material in Scheme 6 is the chloroacyl compound (XLV) whichcan be prepared by literature methods (e.g. the method described in J.Med. Chem., 2004, 47, 3924-3926) or methods analogous thereto. Compound(XLV) is converted into the secondary alcohol (XLVI) by reduction with ahydride reducing agent such as sodium borohydride in a polar solventsuch as water/tetrahydrofuran.

The secondary alcohol (XLVI) can then be reacted with a phenoliccompound of the formula R¹—OH under Mitsunobu alkylation conditions,e.g. in the presence of diethyl azodicarboxylate and triphenylphosphine,as described above, to give the aryl ether compound (XLVII).

The chorine atom in the aryl ether compound (XLVII) is then displaced byreaction with an amine HNR²R³ to give a compound of the formula(XLVIII). The nucleophilic displacement reaction may be carried out byheating the amine with the aryl ether in a polar solvent such as analcohol at an elevated temperature, for example approximately 100° C.The heating may advantageously be achieved using a microwave heater. Theresulting amine (XLVIII) can then be subjected to a Suzuki couplingprocedure with a boronate of the formula (XV) as described above to givethe compound (XLIX).

In a variation on the reaction sequence shown in Scheme 6, the secondaryalcohol (XLVI) can be subjected to a nucleophilic displacement reactionwith an amine HNR²R³ before introducing the group R¹ by means of theMitsunobu ether-forming reaction.

Another route to compounds of the formula (I) in which E and R¹ areattached to the same carbon atom in the group A is illustrated in Scheme7.

In Scheme 7, an N-protected pyrazolyl boronic acid (L) is reacted underSuzuki coupling conditions with the cyano compound X-E-CN in which X istypically a halogen such as bromine or chlorine. The protecting group PGat the 1-position of the pyrazole ring may be, for example, atriphenylmethyl (trityl) group. The boronic acid (L) can be preparedusing the method described in EP 1382603 or methods analogous thereto.

The resulting nitrile (LI) may then be reacted with a Grignard reagentR¹—MgBr to introduce the group R¹ and form the ketone (LII). The ketone(LII) is converted to the enamine (LIV) by reaction with thediphenylphosphinoylmethylamine (LIII) in the presence of a strong basesuch as an alkyl lithium, particularly butyl lithium.

The enamine (LIV) is then subjected to hydrogenation over a palladium oncharcoal catalyst to reduce the double bond of the enamine and removethe 1-phenethyl group. Where the protecting group PG is a trityl group,hydrogenation also removes the trityl group, thereby yielding a compoundof the formula (LV).

Alternatively, the enamine (LIV) can be reduced with a hydride reducingagent under the conditions described in Tetrahedron: Asymmetry 14 (2003)1309-1316 and subjected to a chiral separation. Removal of theprotecting 2-phenethyl group and the protecting group PG then gives anoptically active form of the compound of formula (LV).

Intermediates of the formula (X) wherein A and R² link to form a ringcontaining an oxygen atom can be prepared by the general methodillustrated in Scheme 8.

In Scheme 8, a ketone (LVI) is reacted with trimethylsulphonium iodideto form the epoxide (LVII). The reaction is typically carried out in thepresence of a hydride base such as sodium hydride in a polar solventsuch as dimethylsulphoxide.

The epoxide (LVII) is subjected to a ring opening reaction withethanolamine in the presence of a non-interfering base such astriethylamine in a polar solvent such as an alcohol (e.g. isopropanol),usually with mild heating (e.g. up to approximately 50° C. The resultingsecondary alcohol is then cyclised to form the morpholine ring bytreatment with concentrated sulphuric acid in a solvent such asethanolic dichloromethane.

The morpholine intermediate (LIX) can then reacted with the boronate(XV) under Suzuki coupling conditions to give the compound of formula(LX), which corresponds to a compound of the formula (I) in whichA-NR²R³ forms a morpholine group.

Instead of reacting the epoxide (LVII) with ethanolamine, it may insteadbe reacted with mono- or dialkylamines thereby providing a route tocompounds containing the moiety:

Compounds wherein R² and R³ are both hydrogen can be prepared byreacting the epoxide (LVII) with potassium phthalimide in a polarsolvent such as DMSO. During the Suzuki coupling step, the phthalimidegroup may undergo partial hydrolysis to give the correspondingphthalamic acid which can be cleaved using hydrazine to give the aminogroup NH₂. Alternatively, the phthalamic acid can be recyclised to thephthalimide using a standard amide-forming reagent and the phthaloylgroup then removed using hydrazine to give the amine.

A further synthetic route to compounds of the formula (I) wherein A andNR²R³ combine to form a cyclic group is illustrated in Scheme 9.

In Scheme 9, the starting material (LXI) is typically adi-aryl/heteroaryl methane in which one or both of the aryl/heteroarylgroups is capable of stabilising or facilitating formation of an anionformed on the methylene group between E and R¹. For example, R¹ mayadvantageously be a pyridine group. The starting material (LXI) isreacted with the N-protected bis-2-chloroethylamine (LXII) in thepresence of a non-interfering strong base such as sodiumhexamethyldisilazide in a polar solvent such as tetrahydrofuran at areduced temperature (e.g. around 0° C.) to give the N-protected cyclicintermediate (LXIII). The protecting group can be any standardamine-protecting group such as a Boc group. Following cyclisation, theintermediate (LXIII) is coupled to a boronate of the formula (XV) underSuzuki coupling conditions and then deprotected to give the compound ofthe formula (I).

Compounds of the formula (I) in which the moiety:

is a group:

wherein “Alk” is a small alkyl group such as methyl or ethyl can beformed by the synthetic route illustrated in Scheme 10.

In Scheme 10, a carboxylic acid of the formula (LXIV) is esterified bytreatment with methanol in the presence of an acid catalyst such ashydrochloric acid. The ester (LXV) is then reacted with a strong basesuch as lithium diisopropylamide (LDA) and an alkyl iodide such asmethyl iodide at reduced temperature (e.g. between 0° C. and −78° C.).The branched ester (LXVI) is then hydrolysed to the acid (LXVII) andcoupled with an amine HNR²R³ under standard amide forming conditions ofthe type described above. The amide (LXVIII) can then be reduced to theamine (LXIX) using lithium aluminium hydride, and the amine (LXIX) isthen reacted with a pyrazole boronate or boronic acid under Suzukicoupling conditions to give a compound of the formula (I).

Once formed, many compounds of the formula (I) can be converted intoother compounds of the formula (I) using standard functional groupinterconversions. For example, compounds of the formula (I) in which theNR²R³ forms part of a nitrile group can be reduced to the correspondingamine. Compounds in which NR²R³ is an NH₂ group can be converted to thecorresponding alkylamine by reductive alkylation, or to a cyclic group.Compounds wherein R¹ contains a halogen atom such as chlorine or brominecan be used to introduce an aryl or heteroaryl group substituent intothe R¹ group by means of a Suzuki coupling reaction. Further examples ofinterconversions of one compound of the formula (I) to another compoundof the formula (I) can be found in the examples below. Additionalexamples of functional group interconversions and reagents andconditions for carrying out such conversions can be found in, forexample, Advanced Organic Chemistry, by Jerry March, 4^(th) edition,119, Wiley Interscience, New York, Fiesers' Reagents for OrganicSynthesis, Volumes 1-17, John Wiley, edited by Mary Fieser (ISBN:0-471-58283-2), and Organic Syntheses, Volumes 1-8, John Wiley, editedby Jeremiah P. Freeman (ISBN: 0-471-31192-8).

In many of the reactions described above, it may be necessary to protectone or more groups to prevent reaction from taking place at anundesirable location on the molecule. Examples of protecting groups, andmethods of protecting and deprotecting functional groups, can be foundin Protective Groups in Organic Synthesis (T. Green and P. Wuts; 3rdEdition; John Wiley and Sons, 1999).

A hydroxy group may be protected, for example, as an ether (—OR) or anester (—OC(═O)R), for example, as: a t-butyl ether, a benzyl, benzhydryl(diphenylmethyl), or trityl (triphenylmethyl) ether; a trimethylsilyl ort-butyldimethylsilyl ether; or an acetyl ester (—OC(═O)CH₃, —OAc). Analdehyde or ketone group may be protected, for example, as an acetal(R—CH(OR)₂) or ketal (R₂C(OR)₂), respectively, in which the carbonylgroup (>C═O) is converted to a diether (>C(OR)₂), by reaction with, forexample, a primary alcohol. The aldehyde or ketone group is readilyregenerated by hydrolysis using a large excess of water in the presenceof acid. An amine group may be protected, for example, as an amide(—NRCO—R) or a urethane (—NRCO—OR), for example, as: a methyl amide(—NHCO—CH₃); a benzyloxy amide (—NHCO—OCH₂C₈H₅, —NH-Cbz); as a t-butoxyamide (—NHCO—OC(CH₃)₃, —NH-Boc); a 2-biphenyl-2-propoxy amide(—NHCO—OC(CH₃)₂C₆H₄C₆H₅, —NH-Bpoc), as a 9-fluorenylmethoxy amide(—NH-Fmoc), as a 6-nitroveratryloxy amide (—NH-Nvoc), as a2-trimethylsilylethyloxy amide (—NH-Teoc), as a 2,2,2-trichloroethyloxyamide (—NH-Troc), as an allyloxy amide (—NH-Alloc), or as a2-(phenylsulphonyl)ethyloxy amide (—NH-Psec). Other protecting groupsfor amines, such as cyclic amines and heterocyclic N—H groups, includetoluenesulphonyl (tosyl) and methanesulphonyl (mesyl) groups and benzylgroups such as a para-methoxybenzyl (PMB) group. A carboxylic acid groupmay be protected as an ester for example, as: an C₁₋₇ alkyl ester (e.g.,a methyl ester, a t-butyl ester); a C₁₋₇ haloalkyl ester (e.g., a C₁₋₇trihaloalkyl ester); a triC₁₋₇alkylsilyl-C₁₋₇alkyl ester, or a C₆₋₂₀aryl-C₁₋₇ alkyl ester (e.g., a benzyl ester; a nitrobenzyl ester); or asan amide, for example, as a methyl amide. A thiol group may beprotected, for example, as a thioether (—SR), for example, as: a benzylthioether an acetamidomethyl ether (—S—CH₂NHC(═O)CH₃).

The 1(H) position of the pyrazole group in the compounds of the formula(I) or its precursors can be protected by a variety of groups, theprotecting group being selected according to the nature of the reactionconditions to which the group is exposed. Examples of protecting groupsfor the pyrazole N—H include tetrahydropyranyl, benzyl and4-methoxybenzyl groups.

Ancillary Compounds for Use According to the Invention

Any of a wide variety of ancillary compounds may be used in thecombinations of the invention. Particular examples are described indetail in sections 1 to 18, below.

Preferably, the ancillary compound(s) is (are) selected from Groups A toE, set out below:

Group A

In one aspect of the invention, the ancillary compound for use incombination with the compounds that have protein kinase B (PKB) and/orprotein kinase A (PKA) inhibiting or modulating activity of theinvention are independently selected from the following classes:

-   -   1. signalling inhibitors;    -   2. ancillary PKB inhibitors;    -   3. CDK inhibitors;    -   4. COX-2 inhibitors;    -   5. HDAC inhibitors;    -   6. DNA methyltransferase inhibitors;    -   7. proteosome inhibitors;    -   8. a combination of two or more of the foregoing classes.

A reference to a particular ancillary compound herein (for example, areference to a signalling inhibitor, ancillary PKB inhibitor, CDKinhibitors, COX-2 inhibitors, HDAC inhibitor, DNA methyltransferaseinhibitor or proteosome inhibitor) is intended to include ionic, salt,solvate, isomers, tautomers, N-oxides, ester, prodrugs, isotopes andprotected forms thereof (preferably the salts or tautomers or isomers orN-oxides or solvates thereof, and more preferably, the salts ortautomers or N-oxides or solvates thereof).

Group B: Cytotoxic Compounds

In another aspect of the invention, the ancillary compound for use withthe compounds that have protein kinase B (PKB) and/or protein kinase A(PKA) inhibiting or modulating activity of the invention is a cytotoxiccompound. Cytotoxicity may be assayed or determined using any of a widevariety of techniques well-known to those skilled in the art.

Preferably, the cytotoxic compound for use in combination with thecompounds that have protein kinase B (PKB) and/or protein kinase A (PKA)inhibiting or modulating activity of the invention is selected from thefollowing classes:

-   -   1. camptothecin compounds;    -   2. antimetabolites;    -   3. vinca alkaloids;    -   4. taxanes;    -   5. platinum compounds;    -   6. DNA binders and Topo II inhibitors (including anthracycline        derivatives);    -   7. alkylating agents (including aziridine, nitrogen mustard and        nitrosourea alkylating agents);    -   8. a combination of two or more of the foregoing classes.

Epothilones constitute another class of suitable cytotoxic agents foruse in combination with the compounds that have protein kinase B (PKB)and/or protein kinase A (PKA) inhibiting or modulating activity of theinvention. Accordingly, the cytotoxic compound for use in combinationwith the compounds that have protein kinase B (PKB) and/or proteinkinase A (PKA) inhibiting or modulating activity of the invention may beselected from the following classes:

-   -   1. camptothecin compounds;    -   2. antimetabolites;    -   3. vinca alkaloids;    -   4. taxanes;    -   5. epothilones;    -   6. platinum compounds;    -   7. DNA binders and Topo II inhibitors (including anthracycline        derivatives);    -   8. alkylating agents (including aziridine, nitrogen mustard and        nitrosourea alkylating agents);    -   9. a combination of two or more of the foregoing classes.

A reference to a particular cytotoxic compound herein (for example, areference to a camptothecin compound, antimetabolite, vinca alkaloid,taxane, platinum compound, DNA binder, Topo II inhibitor (includinganthracycline derivatives), as well as alkylating agents (including theaziridine, nitrogen mustard and nitrosourea alkylating agents) isintended to include ionic, salt, solvate, isomers, tautomers, N-oxides,ester, prodrugs, isotopes and protected forms thereof (preferably thesalts or tautomers or isomers or N-oxides or solvates thereof, and morepreferably, the salts or tautomers or N-oxides or solvates thereof).

Group C: Monoclonal Antibodies

In another aspect of the invention, the ancillary compound for use withthe compounds that have protein kinase B (PKB) and/or protein kinase A(PKA) inhibiting or modulating activity of the invention is a monoclonalantibody. Any monoclonal antibody (e.g. to one or more cell surfaceantigen(s)) may be used in combination with the compounds that haveprotein kinase B (PKB) and/or protein kinase A (PKA) inhibiting ormodulating activity of the invention. Antibody specificity may beassayed or determined using any of a wide variety of techniqueswell-known to those skilled in the art.

Group D

In another aspect of the invention, the ancillary compound for use incombination with the compounds that have protein kinase B (PKB) and/orprotein kinase A (PKA) inhibiting or modulating activity of theinvention is selected from the following classes:

-   -   1. hormones, hormone agonists, hormone antagonists and hormone        modulating agents (including antiandrogens, antiestrogens and        GNRAs);    -   2. cytokines and cytokine activating agents;    -   3. retinoids;    -   4. a combination of two or more of the foregoing classes.

A reference to a particular ancillary compound herein (for example, areference to a hormone, hormone agonist, hormone antagonist, hormonemodulating agent, cytokine, cytokine activating agent and retinoid) isintended to include ionic, salt, solvate, isomers, tautomers, N-oxides,ester, prodrugs, isotopes and protected forms thereof (preferably thesalts or tautomers or isomers or N-oxides or solvates thereof, and morepreferably, the salts or tautomers or N-oxides or solvates thereof).

Group E: Multiple Combinations

In another aspect of the invention, two or more ancillary compounds areused in combination with the compounds that have protein kinase B (PKB)and/or protein kinase A (PKA) inhibiting or modulating activity of theinvention, and in such embodiments the two or more ancillary compoundsmay be independently selected from the following classes:

-   -   1. hormones, hormone agonists, hormone antagonists and hormone        modulating agents (including antiandrogens, antiestrogens and        GNRAs);    -   2. cytokines and cytokine activating agents;    -   3. retinoids;    -   4. a combination of two or more of the foregoing classes (1) to        (3);    -   5. monoclonal antibodies;    -   6. camptothecin compounds;    -   7. antimetabolites;    -   8. vinca alkaloids;    -   9. taxanes;    -   10. epothilones    -   11. platinum compounds;    -   12. DNA binders and Topo II inhibitors (including anthracycline        derivatives);    -   13. alkylating agents (including aziridine, nitrogen mustard and        nitrosourea alkylating agents);    -   14. a combination of two or more of the foregoing classes        (6)-(12).    -   15. signalling inhibitors;    -   16. ancillary PKB inhibitors;    -   17. CDK inhibitors;    -   18. COX-2 inhibitors;    -   19. HDAC inhibitors;    -   20. DNA methylase inhibitors;    -   21. proteosome inhibitors;    -   22. a combination of two or more of the foregoing classes        (14)-(20);    -   23. a combination of two or more of the foregoing classes        (1)-(21).

A reference to a particular ancillary compound herein is intended toinclude ionic, salt, solvate, isomers, tautomers, N-oxides, ester,prodrugs, isotopes and protected forms thereof (preferably the salts ortautomers or isomers or N-oxides or solvates thereof, and morepreferably, the salts or tautomers or N-oxides or solvates thereof).

1. Hormones, Hormone Agonists, Hormone Antagonists and HormoneModulating Agents

Definition:

The terms “antiandrogen”, “antiestrogen”, “antiandrogen agent” and“antiestrogen agent” as used herein refers to those described herein andanalogues thereof, including the ionic, salt, solvate, isomers,tautomers, N-oxides, ester, prodrugs, isotopes and protected formsthereof (preferably the salts or tautomers or isomers or N-oxides orsolvates thereof, and more preferably, the salts or tautomers orN-oxides or solvates thereof), as described above.

Biological Activity:

The hormones, hormone agonists, hormone antagonists and hormonemodulating agents (including the antiandrogens and antiestrogen agents)working via one or more pharmacological actions as described herein havebeen identified as suitable anti-cancer agents.

Technical Background:

Hormonal therapy plays an important role in the treatment of certaintypes of cancer where tumours are formed in tissues that are sensitiveto hormonal growth control such as the breast and prostate. Thus, forexample, estrogen promotes growth of certain breast cancers andtestosterone promotes growth of some prostate cancers. Since the growthof such tumours is dependent on specific hormones, considerable researchhas been carried out to investigate whether it is possible to affecttumour growth by increasing or decreasing the levels of certain hormonesin the body. Hormonal therapy attempts to control tumour growth in thesehormone-sensitive tissues by manipulating the activity of the hormones,

With regard to breast cancer, tumour growth is stimulated by estrogen,and antiestrogen agents have therefore been proposed and widely used forthe treatment of this type of cancer. One of the most widely used ofsuch agents is tamoxifen which is a competitive inhibitor of estradiolbinding to the estrogen receptor (ER). When bound to the ER, tamoxifeninduces a change in the three-dimensional shape of the receptor,inhibiting its binding to the estrogen responsive element on DNA. Undernormal physiological conditions, estrogen stimulation increases tumourcell production of transforming growth cell b (TGF-b), an autocrineinhibitor of tumour cell growth. By blocking these pathways, the neteffect of tamoxifen treatment is to decrease the autocrine stimulationof breast cancer growth. In addition, tamoxifen decreases the localproduction of insulin-like growth factor (IGF-1) by surrounding tissues:IGF-I is a paracrine growth factor for the breast cancer cell (Jordanand Murphy, Endocr. Rev., 1990, 1 1; 578-610). Tamoxifen is theendocrine treatment of choice for post-menopausal women with metastaticbreast cancer or at a high risk of recurrences from the disease.Tamoxifen is also used in pre-menopausal women with ER-positive tumours.There are various potential side-effects of long-term tamoxifentreatment, for example the possibility of endometrial cancer and theoccurrence of thrombo-embolic events.

Other estrogen receptor antagonists or selective estrogen receptormodulators (SERMs) include fulvestrant, toremifene and raloxifene.Fulvestrant which has the chemical name7-α-[9-(4,4,5,5,5-pentafluoropentylsulphinyl)-nonyl]estra-1,3,5-(10)-triene-3,17-beta-diol,is used as a second line treatment of advanced breast cancer butside-effects include hot flushes and endometrial stimulation. Toremifeneis a non-steroidal SERM, which has the chemical name2-(4-[(Z)-4-chloro-1,2-diphenyl-1-butenyl]-phenoxy)-N,N-dimethylethylamine,and is used for the treatment of metastatic breast cancer, side-effectsincluding hot flushes, nausea and dizziness. Raloxifene is abenzothiophene SERM, which has the chemical name[6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thien-3-yl]-[4-[2-(1-piperidinyl)ethoxy]-phenyl]-methanonehydrochloride, and is being investigated for the treatment of breastcancer, side-effects including hot flushes and leg cramps.

With regard to prostate cancer, such cancer cells have a high level ofexpression of androgen receptor, and antiandrogens have therefore beenused to treat the disease. Antiandrogens are androgen receptorantagonists which bind to the androgen receptor and preventdihydrotestosterone from binding. Dihydrotestosterone stimulates newgrowth of prostate cells, including cancerous prostate cells. An exampleof an antiadrogen is bicalutamide, which has the chemical name(R,S)-N-(4-cyano-3-(4-fluorophenylsulfonyl)-2-hydroxy-2-methyl-3-(trifluoromethyl)propanamide,and has been approved for use in combination with luteinizinghormone-releasing hormone (LHRH) analogs for the treatment of advancedprostate cancer, side effects including hot flushes, bone pain,hematuria and gastro-intestinal symptoms.

A further type of hormonal cancer treatment comprises the use ofprogestin analogs. Progestin is the synthetic form of progesterone.Progesterone is a hormone secreted by the ovaries and endometrial liningof the uterus. Acting with estrogen, progesterone promotes breastdevelopment and growth of endometrial cells during the menstrual cycle.It is believed that progestins may act by suppressing the production ofestrogen from the adrenal glands (an alternate source particularly inpost-menopausal women), lowering estrogen receptor levels, or alteringtumour hormone metabolism.

Progestin analogs are commonly used in the management of advanceduterine cancer. They can also be used for treating advanced breastcancer, although this use is less common, due to the numerousanti-estrogen treatment options available. Occasionally, progestinanalogs are used as hormonal therapy for prostate cancer. An example ofa progestin analog is megestrol acetate (a.k.a. megestrel acetate),which has the chemical name17α-acetyloxy-6-methylpregna-4,6-diene-3,20-dione, and is a putativeinhibitor of pituitary gonadotrophin production with a resultantdecrease in estrogen secretion, The drug is used for the palliativetreatment of advanced carcinoma of the breast or endometrium (i.e.,recurrent, inoperable, or metastatic disease), side-effects includingoedema and thromoembolic episodes.

Preferences and Specific Embodiments:

A particularly preferred antiestrogen agent for use in accordance withthe invention is tamoxifen. Tamoxifen is commercially available forexample from AstraZeneca plc under the trade name Nolvadex, or may beprepared for example as described in U.K. patent specifications 1064629and 1354939, or by processes analogous thereto.

Other preferred antiestrogen agents include fulvestrant, raloxifene andtoremifene. Yet another preferred antiestrogen agent is droloxifene.Fulvestrant is commercially available for example from AstraZeneca plcunder the trade name Faslodex, or may be prepared for example asdescribed in European patent specification No. 138504, or by processesanalogous thereto. Raloxifene is commercially available for example fromEli Lilly and Company under the trade name Evista, or may be preparedfor example as described in U.S. Pat. No. 4,418,068, or by processesanalogous thereto. Toremifene is commercially available for example fromSchering Corporation under the trade name Fareston, or may be preparedfor example as described in U.S. Pat. No. 4,696,949, or by processesanalogous thereto. The antiestrogen agent droloxifene, which may beprepared for example as described in U.S. Pat. No. 5,047,431, or byprocesses analogous thereto, can also be used in accordance with theinvention.

A preferred antiandrogen for use in accordance with the invention isbicalutamide which is commercially available for example fromAstraZeneca plc under the trade name Casodex, or may be prepared forexample as described in European patent specification No. 100172, or byprocesses analogous thereto. Other preferred antiandrogens for use inaccordance with the invention include tamoxifen, fulvestrant,raloxifene, toremifene, droloxifene, letrazole, anastrazole, exemestane,bicalutamide, luprolide, megestrol/megestrel acetate, aminoglutethimideand bexarotene.

A preferred progestin analog is megestrol/megestrel acetate which iscommercially available for example from Bristol-Myers Squibb Corporationunder the trade name Megace, or may be prepared for example as describedin U.S. Pat. No. 2,891,079, or by processes analogous thereto.

Thus, specific embodiments of these anti-cancer agents for use in thecombinations of the invention include: tamoxifen; toremifene;raloxifene; medroxyprogesterone; megestrol/megestrel; aminoglutethimide;letrozole; anastrozole; exemestane; goserelin; leuprolide; abarelix;fluoxymestrone; diethylstilbestrol; ketoconazole; fulvestrant;flutamide; bicalutimide; nilutamide; cyproterone and buserelin.

Thus, contemplated for use in the combinations of the invention areantiandrogens and antiestrogens.

In other embodiments, the hormone, hormone agonist, hormone antagonistor hormone modulating agent is fulvestrant, raloxifene, droloxifene,toremifene, megestrol/megestrel and bexarotene.

Posology:

The antiandrogen or antiestrogen agent is advantageously administered ina dosage of about 1 to 100 mg daily depending on the particular agentand the condition being treated. Tamoxifen is advantageouslyadministered orally in a dosage of 5 to 50 mg, preferably 10 to 20 mgtwice a day (or 20 mg once a day), continuing the therapy for sufficienttime to achieve and maintain a therapeutic effect.

With regard to the other preferred antiestrogen agents: fulvestrant isadvantageously administered in the form of a 250 mg monthly injection(though doses of 250-750 mg per month may also be employed); toremifeneis advantageously administered orally in a dosage of about 60 mg once aday, continuing the therapy for sufficient time to achieve and maintaina therapeutic effect; droloxifene is advantageously administered orallyin a dosage of about 20-100 mg once a day; and raloxifene isadvantageously administered orally in a dosage of about 60 mg once aday.

With regard to the preferred antiandrogen bicalutamide, this isgenerally administered in an oral dosage of 50 mg daily.

With regard to the preferred progestin analog megestrol/megestrelacetate, this is generally administered in an oral dosage of 40 mg fourtimes daily.

The dosages noted above may generally be administered for example once,twice or more per course of treatment, which may be repeated for exampleevery 7, 14, 21 or 28 days.

Aromatase Inhibitors

Of the hormones, hormone agonists, hormone antagonists and hormonemodulating agents for use in the combinations of the invention,preferred are aromatase inhibitors.

In post-menopausal women, the principal source of circulating estrogenis from conversion of adrenal and ovarian androgens (androstenedione andtestosterone) to estrogens (estrone and estradiol) by the aromataseenzyme in peripheral tissues. Estrogen deprivation through aromataseinhibition or inactivation is an effective and selective treatment forsome post-menopausal patients with hormone-dependent breast cancer.Examples of such hormone modulating agents include aromatase inhibitorsor inactivators, such as exemestane, anastrozole, letrozole andaminoglutethimide.

Exemestane, which has the chemical name6-methylenandrosta-1,4-diene-3,17-dione, is used for the treatment ofadvanced breast cancer in post-menopausal women whose disease hasprogressed following tamoxifen therapy, side effects including hotflashes and nausea. Anastrozole, which has the chemical name,α,α,α′,α′-tetramethyl-5-(1H-1,2,4-triazol-1-ylmethyl)-1,3-benzenediacetonitrile,is used for adjuvant treatment of post-menopausal women with hormonereceptor-positive early breast cancer, and also for the first-linetreatment of post-menopausal women with hormone receptor-positive orhormone receptor-unknown locally advanced or metastatic breast cancer,and for the treatment of advanced breast cancer in post-menopausal womenwith disease progression following tamoxifen therapy. Administration ofanastozole usually results in side-effects including gastrointestinaldisturbances, rashes and headaches. Letrozole, which has the chemicalname 4,4′-(1H-1,2,4-triazol-1-ylmethylene)-dibenzonitrile, is used forfirst-line treatment of post-menopausal women with hormonereceptor-positive or hormone receptor-unknown locally advanced ormetastatic breast cancer, and for the treatment of advanced breastcancer in post-menopausal women with disease progression followingantiestrogen therapy, possible side-effects including occasionaltransient thrombocytopenia and elevation of liver transaminases.Aminoglutethimide, which has the chemical name3-(4-aminophenyl)-3-ethyl-2,6-piperidinedione, is also used for treatingbreast cancer but suffers from the side-effects of skin rashes and lesscommonly thrombocytopenia and leukopenia.

Preferred aromatase inhibitors include letrozole, anastrozole,exemestane and aminoglutethimide. Letrozole is commercially availablefor example from Novartis A.G. under the trade name Femara, or may beprepared for example as described in U.S. Pat. No. 4,978,672, or byprocesses analogous thereto. Anastrozole is commercially available forexample from AstraZeneca plc under the trade name Arimidex, or may beprepared for example as described in U.S. Pat. No. 4,935,437, or byprocesses analogous thereto. Exemestane is commercially available forexample from Pharmacia Corporation under the trade name Aromasin, or maybe prepared for example as described in U.S. Pat. No. 4,978,672, or byprocesses analogous thereto. Aminoglutethimide is commercially availablefor example from Novartis A.G. under the trade name Cytadren, or may beprepared for example as described in U.S. Pat. No. 2,848,455, or byprocesses analogous thereto. The aromatase inhibitor vorozole, which maybe prepared for example as described in European patent specificationNo. 293978, or by processes analogous thereto, can also be used inaccordance with the invention.

With regard to the preferred aromatase inhihibitors, these are generallyadministered in an oral daily dosage in the range 1 to 1000 mg, forexample letrozole in a dosage of about 2.5 mg once a day; anastrozole ina dosage of about 1 mg once a day; exemestane in a dosage of about 25 mgonce a day; and aminoglutethimide in a dosage of 250 mg 2-4 times daily.

Particularly preferred are aromatase inhibitors selected from the agentsdescribed herein, for example, letrozole, anastrozole, exemestane andaminoglutethimide.

GNRAs

Of the hormones, hormone agonists, hormone antagonists and hormonemodulating agents for use in the combinations of the invention,preferred are agents of the GNRA class.

Definition:

As used herein the term GNRA is intended to definegonadotropin-releasing hormone (GnRH) agonists and antagonists(including those described below), together with the ionic, salt,solvate, isomers, tautomers, N-oxides, ester, prodrugs, isotopes andprotected forms thereof (preferably the salts or tautomers or isomers orN-oxides or solvates thereof, and more preferably, the salts ortautomers or N-oxides or solvates thereof), as described above.

Technical Background:

When released from the hypothalamus in the brain, gonadotropin-releasinghormone (GnRH) agonists stimulate the pituitary gland to producegonadotropins. Gonadotropins are hormones that stimulate androgensynthesis in the testes and estrogen synthesis in the ovaries. When GnRHagonists are first administered, they can cause an increase ingonadotropin release, but with continued administration, GnRH will blockgonadotropin release, and therefore decrease the synthesis of androgenand estrogen. GnRH analogs are used to treat metastatic prostate cancer.They have also been approved for treatment of metastatic breast cancerin pre-menopausal women. Examples of GnRH analogs include goserelinacetate and leuprolide acetate. In contrast GnRH antagonists such asaberelix cause no initial GnRH surge since they have no agonist effects.However, due to their narrow therapeutic index, their use is currentlylimited to advanced prostate cancer that is refractory to other hormonaltreatment such as GnRH agonists and anti-androgens.

Goserelin acetate is a synthetic decapeptide analog of LHRH or GnRH, andhas the chemical structure ispyro-Glu-His-Trp-Ser-Tyr-D-Ser(Bu)-Leu-Arg-Pro-Azgly-NH₂ acetate, and isused for the treatment of breast and prostate cancers and alsoendometriosis, side effects including hot flashes, bronchitis,arrhythmias, hypertension, anxiety and headaches. Leuprolide acetate isa synthetic nonapeptide analog of GnRH or LHRH, and has the chemicalname5-oxo-L-prolyl-L-histidyl-L-tryptophyl-L-seryl-L-tyrosyl-D-leucyl-L-leucyl-L-arginyl-N-ethyl-L-prolinamideacetate. Leuprolide acetate is used for the treatment of prostatecancer, endometriosis, and also breast cancer, side effects beingsimilar to those of goserelin acetate.

Abarelix is a synthetic decapeptideAla-Phe-Ala-Ser-Tyr-Asn-Leu-Lys-Pro-Ala, and has the chemical nameN-Acetyl-3-(2-naphthalenyl)-D-alanyl-4-chloro-D-phenylalanyl-3-(3-pyridinyl)-D-alanyl-L-seryl-N-methyl-L-tyrosyl-D-asparaginyl-L-leucyl-N6-(1-methylethyl)-L-lysyl-L-protyl-D-alaninamide.Abarelix can be prepared according to R. W. Roeske, WO9640757 (1996 toIndiana Univ. Found.).

Preferences and Specific Embodiments:

Preferred GnRH agonists and antagonists for use in accordance with theinvention include any of the GNRAs described herein, including inparticular goserelin, leuprolide/leuporelin, triptorelin, buserelin,abarelix, goserelin acetate and leuprolide acetate. Particularlypreferred are goserelin and leuprolide. Goserelin acetate iscommercially available for example from AstraZeneca plc under the tradename Zoladex, or may be prepared for example as described in U.S. Pat.No. 5,510,460, or by processes analogous thereto. Leuprolide acetate iscommercially available for example from TAP Pharmaceuticals Inc. underthe trade name Lupron, or may be prepared for example as described inU.S. Pat. No. 3,914,412, or by processes analogous thereto. Goserelin iscommercially available from AstraZeneca under the trade name Zoladex maybe prepared for example as described in ICI patent publication US4100274or Hoechst patent publication EP475184 or by processes analagousthereto. Leuprolide is commercially available in the USA from TAPPharmaceuticals Inc. under the trade name Lupron and in Europe fromWyeth under the trade name Prostap and may be prepared for example asdescribed in Abbott patent publication US4005063 or by processesanalogous thereto. Triptorelin is commercially available from WatsonPharma under the trade name Trelstar and may be prepared for example asdescribed in Tulane patent publication US5003011 or by processesanalagous thereto. Buserelin is commercially available under the tradename Suprefact and may be prepared for example as described in Hoechstpatent publication U.S. Pat. No. 4,024,248 or by processes analogousthereto. Abarelix is commercially available from Praecis Pharmaceuticalsunder the trade name Plenaxis and may be prepared for example asdescribed by Jiang at al., J Med Chem (2001), 44(3), 453-467 orPolypeptide Laboratories patent publication WO2003055900 or by processesanalogous thereto.

Other GnRH agonists and antagonists for use in accordance with theinvention include, but are not limited to, Histrelin from OrthoPharmaceutical Corp, Nafarelin acetate from Roche, and Deslorelin fromShire Pharmaceuticals.

Posology:

The GnRH agonists and antagonists are advantageously administered indosages of 1.8 mg to 100 mg, for example 3.6 mg monthly or 10.8 mg everythree months for goserelin or 7.5 mg monthly, 22.5 mg every three monthsor 30 mg every four months for leuprolide.

With regard to the preferred GnRH analogs, these are generallyadministered in the following dosages, namely goserelin acetate as a 3.6mg subcutaneous implant every 4 weeks, and leuprolide as a 7.5 mgintramuscular depot every month.

2. Cytokines and Cytokine-Activating Agents

Definition:

The term “cytokine” is a term of art, and references to cytokines hereinis intended to cover the cytokine per se together with the ionic, salt,solvate, isomers, tautomers, N-oxides, ester, prodrugs, isotopes andprotected forms thereof (preferably the salts or tautomers or isomers orN-oxides or solvates thereof, and more preferably, the salts ortautomers or N-oxides or solvates thereof), as described above. The term“cytokine-activating agent” is intended to cover any agent which(directly or indirectly) induces, potentiates, stimulates, activates orpromotes endogenous cytokine production or the activity thereof in vivo,together with the ionic, salt, solvate, isomers, tautomers, N-oxides,ester, prodrugs, isotopes and protected forms thereof (preferably thesalts or tautomers or isomers or N-oxides or solvates thereof, and morepreferably, the salts or tautomers or N-oxides or solvates thereof), asdescribed above.

Technical Background:

Cytokines are a class of proteins or polypeptides predominantly producedby cells of the immune system which have the capacity to control thefunction of a second cell. In relation to anticancer therapy cytokinesare used to control the growth or kill the cancer cells directly and tomodulate the immune system more effectively to control the growth oftumours.

Cytokines, such interferon (IFN) alpha and IL-6, have been shown tointeract directly with tumor cells, inducing growth arrest or apoptoticcell death. IFN-alpha is used the treatment of malignant melanoma,chronic myelogenous leukemia (CML), hairy cell leukemia, and Kaposi'ssarcoma.

Cytokines also have antitumour actions by stimulating immune cells tofight tumors through a variety of different pathways. For example, the Tcell growth factor, IL-2 promotes T-cell and natural killer (NK) cellgrowth. Other cytokines such as the interferons andgranulocyte-macrophage colony-stimulating factor (GM-CSF) act on antigenpresenting cells to facilitate the activation of the key immune effectorB cells and T cells.

IL-2 is used in both metastatic melanoma and renal cell carcinoma eitheralone or in combination with IFN-alpha. In particular in late stagekidney cancer IL-2 is the treatment of choice.

Preferences and Specific Embodiments:

Any of the cytokines and cytokine-modulating agents described herein mayfind application in the invention, including in particular interferons(such as interferon-γ and interferon α) and interleukins (e.g.interleukin 2). Interferon α-2b (recombinant) is available commerciallyunder the trade name of INTRON® A from Schering Plough.

Other preferred interferons include Interferon α-2a which is availableunder the trade name of ROFERON from Roche.

A particularly preferred interleukin is PROLEUKIN® IL-2 (aldesleukin)which is available from Chiron Corp.

Posology:

The interferons are administered by injection in a schedule which isdependent on tha particular indication. For IntronA treatment ofmalignant melanoma preferably in a schedule that includes inductiontreatment 5 consecutive days per week for 4 weeks as an intravenous (IV)infusion at a dose of 20 million IU/m2, followed by maintenancetreatment three times per week for 48 weeks as a subcutaneous (SC)injection, at a dose of 10 million IU/m2. For intron A treatment ofnon-Hodgkin's Lymphoma preferably in a schedule of 5 million IUsubcutaneously three times per week for up to 18 months in conjunctionwith an anthracycline-containing chemotherapy regimen.

The recommended initial dose of Roferon-A for CML is 9 MIU dailyadministered as a subcutaneous or intramuscular injection. Based onclinical experience short-term tolerance may be improved by graduallyincreasing the dose of Roferon-A over the first week of administrationfrom 3 MIU daily for 3 days to 6 MIU daily for 3 days to the target doseof 9 MIU daily for the duration of the treatment period. The inductiondose of Roferon-A for Hairy cell leukaemia is 3 MIU daily for 16 to 24weeks, administered as a subcutaneous or intramuscular injection.Subcutaneous administration is particularly suggested for, but notlimited to, thrombocytopenic patients (platelet count <50,000) or forpatients at risk for bleeding. The recommended maintenance dose is 3MIU, three times a week (tiw).

For PROLEUKIN the following schedule has been used to treat adultpatients with metastatic renal cell carcinoma (metastatic RCC) ormetastatic melanoma (each course of treatment consists of two 5-daytreatment cycles separated by a rest period): 600,000 IU/kg (0.037mg/kg) dose administered every 8 hours by a 15-minute IV infusion for amaximum of 14 doses. Following 9 days of rest, the schedule is repeatedfor another 14 doses, for a maximum of 28 doses per course, astolerated.

Cytokine-Activating Agents:

Preferred cytokine-activating agents include: (a) Picibanil from ChugaiPharmaceuticals, an IFN-gamma-inducing molecule for carcinoma treatment;(b) Romurtide from Daiichi which activates the cytokine network bystimulation of colony stimulating factor release; (c) Sizofiran fromKaken Pharmaceutical, a beta1-3, beta1-6 D-glucan isolated fromsuehirotake mushroom, which stimulates production of IFN-gamma and IL-2by mitogen-stimulated peripheral blood mononuclear cells, and is usefulin uterine cervix tumour and lung tumour treatment; (d) Virulizin fromLorus Therapeutics Inc, a NK agonist and cytokine release modulatorwhich stimulates IL-17 synthesis and IL-12 release for the treatment ofsarcoma, melanoma, pancreas tumours, breast tumours, lung tumours, andKaposis sarcoma Phase III pancreatic; and (e) Thymosin alpha 1, asynthetic 28-amino acid peptide with multiple biological activitiesprimarily directed towards immune response enhancement for increasedproduction of Th1 cytokines, which is useful in the treatment ofnon-small-cell lung cancer, hepatocellular carcinoma, melanoma,carcinoma, and lung brain and renal tumours.

3. Retinoids

Definition:

The term “retinoid” is a term of art used herein in a broad sense toinclude not only the specific retinoids disclosed herein, but also theionic, salt, solvate, isomers, tautomers, N-oxides, ester, prodrugs,isotopes and protected forms thereof (preferably the salts or tautomersor Isomers or N-oxides or solvates thereof, and more preferably, thesalts or tautomers or N-oxides or solvates thereof), as described above.

Technical Background:

Tretinoin is an endogenous metabolite of retinol. It induces terminaldifferentiation in several hemopoietic precursor cell lines, includinghuman myeloid lines. Acute Promyelocytic Leukemia (APL) is associatedwith a specific translocation between chromosomes 15 and 17; theretinoic acid receptor—α is located on chromosome 17. The translocationappears in inhibit differentiation and lead to carcinogenesis; tretinoinmay overcome this when used in high doses. Tretinoin induces remissionsin 64-100% of APL patients, with time to remission usually between 8 and119 days of therapy. Acquired resistance during therapy is commonespecially with prolonged dosing (4-6 months). Alitretinoin is a9-cis-retinoic acid derivative which appears to be selective for the RXRsubfamily of retinoid receptors. This selectivity may preservetherapeutic antineoplastic effects while reducing significant sideeffects of retinoid therapy including birth defects at fetal exposure,irritation of skin and mucosal surfaces or skeletal abnormalities.Topical alitretinoin is approved in the US for the treatment of Kaposi'sSarcoma. Oral and gel (topical) formulations of bexarotene (Targretin;LGD-1069), a retinoid X receptor (RXR)-selective antitumor retinoid, areavailable for the treatment of cutaneous T-cell lymphoma (CTCL).

U.S. Pat. No. 6,127,382, WO 01/70668, WO 00/68191, WO 97/48672, WO97/19052 and WO 97/19062 (all to Allergan) each describe compoundshaving retinoid-like activity for use in the treatment of varioushyperproliferative diseases including cancers.

Preferences and Specific Embodiments:

Preferred retinoids for use in accordance with the invention Include anyof the retinoids disclosed herein, including in particular tretinoin(all-trans retinoic acid), alitretinoin and bexarotene. Tretinoin(Retacnyl, Aknoten, Tretin M) is commercially available from Roche underthe trade name Vesanoid and may be prepared for example as described inD. A. van Dorp, J. R. Arens, Rec. Trav. Chim. 65, 338 (1946); C. D.Robeson et al., J. Am. Chem. Soc. 77, 4111 (1955); R. Marbet, DE2061507; U.S. Pat. No. 3,746,730 (1971, 1973 both to Hoffmann-La Roche),or by processes analogous thereto. Alitretinoin (9-cis-Tretinoln,Panrexin) is commercially available from Ligand Pharmaceuticals underthe trade name Panretin and may be prepared for example as described inC. D. Robeson et al., J. Am. Chem. Soc. 77, 4111 (1955); M. Matsui etal., J. Vitaminol. 4, 178 (1958); M. F. Boehm et al., J. Med. Chem. 37,408 (1994), or by processes analogous thereto. Bexarotene (Targrexin,Targret) is commercially available from Ligand Pharmaceuticals under thetrade name Targretin and may be prepared for example as described in M.F. Boehm et al., WO 9321146 (1993 to Ligand Pharm.); M. L. Dawson etal., U.S. Pat. No. 5,466,861 (1995 to SRI Int.; La Jolla Cancer Res.Found.), or by processes analogous thereto.

Posology:

Tretinoin is advantageously administered in dosages of 25 mg/m²/day to45 mg/m²/day by mouth in two divided doses for 30 days after completeremission or up to a maximum of 90 days. Alitretinoin gel 0.1% isadvantageously administered initially by application two (2) times a dayto cutaneous KS lesions. Bexarotene is advantageously administeredinitially as a single daily oral dose of 300 mg/m²/day. The dose may beadjusted to 200 mg/m²/day then to 100 mg/m²/day, or temporarilysuspended, if necessitated by toxicity. If there is no tumor responseafter eight weeks of treatment and if the initial dose of 300 mg/m²/dayis well tolerated, the dose may be escalated to 400 mg/m²/day withcareful monitoring. Bexarotene gel is advantageously applied initiallyonce every other day for the first week. The application frequency maybe increased at weekly intervals to once daily, then twice daily, thenthree times daily and finally four times daily according to individuallesion tolerance.

4. Monoclonal Antibodies.

Any monoclonal antibody (e.g. to one or more cell surface antigen(s))may be used in the combinations of the invention. Antibody specificitymay be assayed or determined using any of a wide variety of techniqueswell-known to those skilled in the art.

Definition:

The term “monoclonal antibody” used herein refers to antibodies from anysource, and so includes those that are fully human and also those whichcontain structural or specificity determining elements derived fromother species (and which can be referred to as, for example, chimeric orhumanized antibodies).

Technical Background:

The use of monoclonal antibodies is now widely accepted in anticancerchemotherapy as they are highly specific and can therefore bind andaffect disease specific targets, thereby sparing normal cells andcausing fewer side-effects than traditional chemotherapies.

One group of cells which have been investigated as targets for antibodychemotherapy for the treatment of various cancers are those bearing thecell-surface antigens comprising the cluster designation (CD) moleculeswhich are over-expressed or aberrantly expressed in tumour cells, forexample CD20, CD22, CD33 and CD52 which are over-expressed on the tumourcell surface, most notably in tumours of hematopoietic origin.Antibodies to these CD targets (anti-CD antibodies) Include themonoclonal antibodies rituximab (a.k.a. rituxamab), tositumomab andgemtuzumab ozogamicin.

Rituximab/rituxamab is a mouse/human chimeric anti-CD20 monoclonalantibody which has been used extensively for the treatment of B-cellnon-Hodgkin's lymphoma including relapsed, refractory low-grade orfollicular lymphoma. The product is also being developed for variousother indications Including chronic lymphocytic leukaemia. Side effectsof rituximab/rituxamab may include hypoxia, pulmonary infiltrates, acuterespiratory distress syndrome, myocardial infarction, ventricularfibrillation or cardiogenic shock. Tositumomab is a cell-specificanti-CD20 antibody labelled with iodine-131, for the treatment ofnon-Hodgkin's lymphoma and lymphocytic leukaemia. Possible side-effectsof tositumomab include thrombocytopenia and neutropenia. Gemtuzumabozogamicin is a cytotoxic drug (calicheamicin) linked to a humanmonoclonal antibody specific for CD33. Calicheamicin is a very potentantitumour agent, over 1,000 times more potent than adriamycin. Oncereleased inside the cell, calicheamicin binds in a sequence-specificmanner to the minor groove of DNA, undergoes rearrangement, and exposesfree radicals, leading to breakage of double-stranded DNA, and resultingin cell apoptosis (programmed cell death). Gemtuzumab ozogamicin is usedas a second-line treatment for acute myeloid leukaemia, possibleside-effects including severe hypersensitivity reactions such asanaphylaxis, and also hepatotoxicity.

Alemtuzumab (Millennium Pharmaceuticals, also known as Campath) is ahumanized monoclonal antibody against CD52 useful for the treatment ofchronic lymphocytic leukaemia and Non-Hodgkin lymphoma which induces thesecretion of TNF-alpha, IFN-gamma and IL-6.

Preferences:

Preferred monoclonal antibodies for use according to the inventioninclude anti-CD antibodies, including alemtuzumab, CD20, CD22 and CD33.Particularly preferred are monoclonal antibody to cell surface antigens,including anti-CD antibodies (for example, CD20, CD22, CD33) asdescribed above.

Specific Embodiments:

In one embodiment, the monoclonal antibody is an antibody to the clusterdesignation CD molecules, for example, CD20, CD22, CD33 and CD52. Inanother embodiment, the monoclonal antibody to cell surface antigen isselected from rituximab/rituxamab, tositumomab and gemtuzumabozogamicin. Other monoclonal antibodies that may be used according tothe invention include bevacizumab.

Exemplary Formulations:

Monoclonal antibodies to cell surface antigen(s) for use according tothe invention include CD52 antibodies (e.g. alemtuzumab) and otheranti-CD antibodies (for example, CD20, CD22 and CD33), as describedherein. Preferred are therapeutic combinations comprising a monoclonalantibody to cell surface antigen(s), for example anti-CD antibodies(e.g. CD20, CD22 and CD33) which exhibit an advantageous efficaciouseffect, for example, against tumour cell growth, in comparison with therespective effects shown by the individual components of thecombination.

Preferred examples of monoclonal antibodies to cell surface antigens(anti-CD antibodies) include rituximab/rituxamab, tositumomab andgemtuzumab ozogamicin. Rituximab/rituxamab is commercially availablefrom F Hoffman-La Roche Ltd under the trade name Mabthera, or may beobtained as described in PCT patent specification No. WO 94/11026.Tositumomab is commercially available from GlaxoSmithKline plc under thetrade name Bexxar, or may be obtained as described in U.S. Pat. No.5,595,721. Gemtuzumab ozogamicin is commercially available from WyethResearch under the trade name Mylotarg, or may be obtained as describedin U.S. Pat. No. 5,877,296.

Biological Activity:

Monoclonal antibodies (e.g. monoclonal antibodies to one or more cellsurface antigen(s)) have been identified as suitable anti-cancer agents.Antibodies are effective through a variety of mechanisms. They can blockessential cellular growth factors or receptors, directly induceapoptosis, bind to target cells or deliver cytotoxic payloads such asradioisotopes and toxins.

Posology:

The anti-CD antibodies may be administered for example in dosages of 5to 400 mg per square meter (mg/m²) of body surface; in particulargemtuzumab ozogamicin may be administered for example in a dosage ofabout 9 mg/m² of body surface; rituximab/rituxamab may be administeredfor example in a dosage of about 375 mg/m² as an IV infusion once a weekfor four doses; the dosage for tositumomab must be individuallyquantified for each patient according to the usual clinical parameterssuch as age, weight, sex and condition of the patient.

These dosages may be administered for example once, twice or more percourse of treatment, which may be repeated for example every 7, 14, 21or 28 days.

5. Camptothecin Compounds

Definition:

The term “camptothecin compound” as used herein refers to camptothecinper se or analogues of camptothecin as described herein, including theionic, salt, solvate, isomers, tautomers, N-oxides, ester, prodrugs,isotopes and protected forms thereof (preferably the salts or tautomersor isomers or N-oxides or solvates thereof, and more preferably, thesalts or tautomers or N-oxides or solvates thereof), as described above.

Technical Background:

Camptothecin compounds are compounds related to or derived from theparent compound camptothecin which is a water-insoluble alkaloid derivedfrom the Chinese tree Camptothecin acuminata and the Indian treeNothapodytes foetida. Camptothecin has a potent inhibitory activityagainst DNA biosynthesis and has shown high activity against tumour cellgrowth in various experimental systems. Its clinical use in anti-cancertherapy is however, limited significantly by its high toxicity, andvarious analogues have been developed in attempts to reduce the toxicityof camptothecin while retaining the potency of its anti-tumour effect.Examples of such analogues include irinotecan and topotecan.

These compounds have been found to be specific inhibitors of DNAtopoisomerase I. Topoisomerases are enzymes that are capable of alteringDNA topology in eukaryotic cells. They are critical for importantcellular functions and cell proliferation. There are two classes oftopoisomerases in eukaryotic cells, namely type I and type II.Topoisomerase I is a monomeric enzyme having a molecular weight ofapproximately 100,000. The enzyme binds to DNA and introduces atransient single-strand break, unwinds the double helix (or allows it tounwind) and subsequently reseals the break before dissociating from theDNA strand.

Irinotecan, namely7-ethyl-10-(4-(1-piperidino)-1-piperidino)carbonyloxy-(20S)-camptothecin,and its hydrochloride, also known as CPT 11, have been found to haveimproved potency and reduced toxicity, and superior water-solubility.Irinotecan has been found to have clinical efficacy in the treatment ofvarious cancers especially colorectal cancer. Another importantcamptothecin compound is topotecan, namely(S)-9-dimethylaminomethyl-10-hydroxy-camptothecin which, in clinicaltrials, has shown efficacy against several solid tumours, particularlyovarian cancer and non-small cell lung carcinoma.

Exemplary Formulations:

A parenteral pharmaceutical formulation for administration by injectionand containing a camptothecin compound can be prepared by dissolving 100mg of a water soluble salt of the camptothecin compound (for example acompound as described in EP 0321122 and in particular the examplestherein) in 10 ml of sterile 0.9% saline and then sterilising thesolution and filling the solution into a suitable container.

Biological Activity:

The camptothecin compounds of the combinations of the invention arespecific inhibitors of DNA topoisomerase I are described above and haveactivity against various cancers.

Prior Art References:

WO 01/64194 (Janssen) discloses combinations of famesyl transferaseinhibitors and camptothecin compounds. EP 137145 (Rhone Poulenc Rorer)discloses camptothecin compounds including irinotecan. EP 321122(SmithKline Beecham) discloses camptothecin compounds includingtopotecan.

Problems:

Although camptothecin compounds have widely used as chemotherapeuticagents in humans, they are not therapeutically effective in all patientsor against all types of tumours. There is therefore a need to increasethe inhibitory efficacy of camptothecin compounds against tumour growthand also to provide a means for the use of lower dosages of camptothecincompounds to reduce the potential for adverse toxic side effects to thepatient.

Preferences:

Preferred camptothecin compounds for use in accordance with theinvention include irinotecan and topotecan referred to above. Irinotecanis commercially available for example from Rhone-Poulenc Rorer under thetrade name “Campto” and may be prepared for example as described inEuropean patent specification No. 137145 or by processes analogousthereto. Topotecan is commercially available for example from SmithKlineBeecham under the trade name “Hycamtin” and may be prepared for exampleas described in European patent number 321122 or by processes analogousthereto. Other camptothecin compounds may be prepared in conventionalmanner for example by processes analogous to those described above foririnotecan and topotecan.

Specific Embodiments:

In one embodiment, the camptothecin compound is irinotecan. In anotherembodiment, the camptothecin compound is a camptothecin compound otherthan irinotecan, for example a camptothecin compound such as topotecan.

Posology:

The camptothecin compound is advantageously administered in a dosage of0.1 to 400 mg per square meter (mg/m²) of body surface area, for example1 to 300 mg/m², particularly for irinotecan in a dosage of about 100 to350 mg/m² and for topotecan in about 1 to 2 mg/m² per course oftreatment. These dosages may be administered for example once, twice ormore per course of treatment, which may be repeated for example every 7,14, 21 or 28 days.

6. Antimetabolites

Definition:

The terms “antimetabolic compound” and “antimetabolite” are used assynonyms and define antimetabolic compounds or analogues ofantimetabolic compounds as described herein, including the ionic, salt,solvate, isomers, tautomers, N-oxides, ester, prodrugs, isotopes andprotected forms thereof (preferably the salts or tautomers or isomers orN-oxides or solvates thereof, and more preferably, the salts ortautomers or N-oxides or solvates thereof), as described above. Thus,the antimetabolic compounds, otherwise known as antimetabolites,referred to herein constitute a large group of anticancer drugs thatinterfere with metabolic processes vital to the physiology andproliferation of cancer cells. Such compounds include nucleosidederivatives, either pyrimidine or purine nucleoside analogs, thatinhibit DNA synthesis, and inhibitors of thymidylate synthase and/ordihydrofolate reductase enzymes.

Technical Background:

Antimetabolites (or antimetabolic compounds), constitute a large groupof anticancer drugs that interfere with metabolic processes vital to thephysiology and proliferation of cancer cells. Such compounds includenucleoside derivatives, either pyrimidine or purine nucleosideanalogues, that inhibit DNA synthesis, and inhibitors of thymidylatesynthase and/or dihydrofolate reductase enzymes. Anti-tumour nucleosidederivatives have been used for many years for the treatment of variouscancers. Among the oldest and most widely used of these derivatives is5-fluorouracil (5-FU) which has been used to treat a number of cancerssuch as colorectal, breast, hepatic and head and neck tumours.

In order to enhance the cytotoxic effect of 5-FU, leucovorin has beenused with the drug to modulate levels of thymidylate synthase which arecritical to ensure that malignant cells are sensitive to the effect of5-FU. However, various factors limit the use of 5-FU, for example tumourresistance, toxicities, including gastrointestinal and haematologicaleffects, and the need for intravenous administration. Various approacheshave been taken to overcome these disadvantages including proposals toovercome the poor bioavailability of 5-FU and also to increase thetherapeutic Index of 5-FU, either by reducing systemic toxicity or byincreasing the amount of active drug reaching the tumour.

One such compound which provides improved therapeutic advantage over5-FU is capecitabine, which has the chemical name[1-(5-deoxy-β-D-ribofuranosyl)-5-fluoro-1,2-dihydro-2-oxo-4-pyrimidinyl]-carbamicacid pentyl ester. Capecitabine is a pro-drug of 5-FU which is wellabsorbed after oral dosing and delivers pharmacologically-activeconcentrations of 5-FU to tumours, with little systemic exposure to theactive drug. As well as offering potentially superior activity to 5-FU,it can also be used for oral therapy with prolonged administration.Another anti-tumour nucleoside derivative is gemcitabine which has thechemical name 2′-deoxy-2′,2′-difluoro-cytidine, and which has been usedin the treatment of various cancers including non-small cell lung cancerand pancreatic cancer. Further anti-tumour nucleosides includecytarabine and fludarabine. Cytarabine, also known as ara-C, which hasthe chemical name 1-β-D-arabinofuranosylcytosine, has been found usefulin the treatment of acute myelocytic leukemia, chronic myelocyticleukemia (blast phase), acute lymphocytic leukemia and erythroleukemia.Fludarabine is a DNA synthesis inhibitor, which has the chemical name9-β-D-arabinofuranosyl-2-fluoro-adenine, and is used for the treatmentof refractory B-cell chronic lymphocytic leukaemia. Otherantimetabolites used in anticancer chemotherapy include the enzymeinhibitors raltitrexed, pemetrexed, and methotrexate. Raltitrexed is afolate-based thymidylate synthase inhibitor, which has the chemical nameN-[5-[N-[(3,4-dihydro-2-methyl-4-oxo-6-quinazolinyl)-methyl-N-methylamino]-2-thenoyl]-L-glutamicacid, and is used in the treatment of advanced colorectal cancer.Pemetrexed is a thymidylate synthase and transferase inhibitor, whichhas the chemical nameN-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-L-glutamicacid, disodium salt, and is used for the treatment of mesothelloma andlocally advanced or metastatic non-small-cell lung cancer (SCLC) inpreviously treated patients. Methotrexate is an antimetabolite whichinterrupts cell division by inhibiting DNA replication throughdihydrofolate reductase inhibition, resulting in cell death, and has thechemical name isN-[4-[[(2,4-diamino-6-pteridinyl)methyl]-ethylamino]benzoyl]-glutamicacid, and is used for the treatment of acute lymphocytic leukemia, andalso in the treatment of breast cancer, epidermoid cancers of the headand neck, and lung cancer, particularly squamous cell and small celltypes, and advanced stage non-Hodgkin's lymphomas.

Biological Activity:

The antimetabolic compounds of the combinations of the inventioninterfere with metabolic processes vital to the physiology andproliferation of cancer cells as described above and have activityagainst various cancers.

Problems:

These anticancer agents have a number of side-effects especiallymyelosuppression and in some cases nausea and diarrhoea. There istherefore a need to provide a means for the use of lower dosages toreduce the potential of adverse toxic side effects to the patient.

Preferences:

Preferred antimetabolic compounds for use in accordance with theinvention include anti-tumour nucleosides such as 5-fluorouracil,gemcitabine, capecitabine, cytarabine and fludarabine and enzymeinhibitors such as railtrexed, pemetrexed and methotrexate referred toherein. Thus, preferred antimetabolic compounds for use in accordancewith the invention are anti-tumour nucleoside derivatives including5-fluorouracil, gemcitabine, capecitabine, cytarabine and fludarabinereferred to herein. Other preferred antimetabolic compounds for use inaccordance with the invention are enzyme inhibitors includingralitrexed, pemetrexed and methotrexate.

5-Fluorouracil is widely available commercially, or may be prepared forexample as described in U.S. Pat. No. 2,802,005. Gemcitabine iscommercially available for example from Eli Lilly and Company under thetrade name Gemzar, or may be prepared for example as described inEuropean patent specification No. 122707, or by processes analogousthereto. Capecitabine is commercially available for example fromHoffman-La Roche Inc under the trade name Xeloda, or may be prepared forexample as described in European patent specification No. 698611, or byprocesses analogous thereto. Cytarabine is commercially available forexample from Pharmacia and Upjohn Co under the trade name Cytosar, ormay be prepared for example as described in U.S. Pat. No. 3,116,282, orby processes analogous thereto. Fludarabine is commercially availablefor example from Schering AG under the trade name Fludara, or may beprepared for example as described in U.S. Pat. No. 4,357,324, or byprocesses analogous thereto. Ralitrexed is commercially available forexample from AstraZeneca plc under the trade name Tomudex, or may beprepared for example as described in European patent specification No.239632, or by processes analogous thereto. Pemetrexed is commerciallyavailable for example from Eli Lilly and Company under the trade nameAlimta, or may be prepared for example as described in European patentspecification No. 432677, or by processes analogous thereto.Methotrexate is commercially available for example from LederleLaboraories under the trade name Methotrexate-Lederle, or may beprepared for example as described In U.S. Pat. No. 2,512,572, or byprocesses analogous thereto. Other antimetabolites for use in thecombinations of the invention include 6-mercapto purine, 6-thioguanine,cladribine, 2′-deoxycoformycin and hydroxyurea.

Specific Embodiments:

In one embodiment, the antimetabolic compound is gemcitabine. In anotherembodiment, the antimetabolic compound is a antimetabolic compound otherthan 5-fluorouracil or fludarabine, for example an antimetaboliccompound such as gemcitabine, capecitabine, cytarabine, ralitrexed,pemetrexed or methotrexate.

Posology:

The antimetabolite compound will be administered in a dosage that willdepend on the factors noted above. Examples of dosages for particularpreferred antimetabolites are given below by way of example. With regardto anti-tumour nucleosides, these are advantageously administered in adaily dosage of 10 to 2500 mg per square meter (mg/m²) of body surfacearea, for example 700 to 1500 mg/m², particularly for 5-FU in a dosageof 200 to 500 mg/m², for gemcitabine in a dosage of 800 to 1200 mg/m²,for capecitabine in a dosage of 1000 to 1200 mg/m², for cytarabine in adosage of 100-200 mg/m² and for fludarabine in a dosage of 10 to 50mg/m².

For the following enzyme inhibitors, examples are given of possibledoses. Thus, raltitrexed can be administered in a dosage of about 3mg/m², pemetrexed in a dosage of 500 mg/m² and methotrexate in a dosageof 30-40 mg/m².

The dosages noted above may generally be administered for example once,twice or more per course of treatment, which may be repeated for exampleevery 7, 14, 21 or 28 days.

7. Vinca Alkaloids

Definition:

The term “vinca alkaloid” as used herein refers to vinca alkaloidcompounds or analogues of vinca alkaloid compounds as described herein,including the ionic, salt, solvate, isomers, tautomers, N-oxides, ester,prodrugs, isotopes and protected forms thereof (preferably the salts ortautomers or isomers or N-oxides or solvates thereof, and morepreferably, the salts or tautomers or N-oxides or solvates thereof), asdescribed above.

Technical Background:

The vinca alkaloids for use in the combinations of the invention areanti-tumour vinca alkaloids related to or derived from extracts of theperiwinkle plant (vinca roses). Among these compounds, vinblastine andvincristine are important clinical agents for the treatment ofleukaemias, lymphomas and testicular cancer, and vinorelbine hasactivity against lung cancer and breast cancer.

Biological Activity:

The vinca alkaloid compounds of the combinations of the invention aretubulin targeting agents and have activity against various cancers.

Problems:

Vinca alkaloids suffer from toxicological effects. For example,vinblastine causes leukopenia which reaches a nadir in 7 to 10 daysfollowing drug administration, after which recovery ensues within 7days, while vincristine demonstrates some neurological toxicity forexample numbness and trembling of the extremities, loss of deep tendonreflexes and weakness of distal limb musculature. Vinorelbine has sometoxicity in the form of granulocytopenia but with only modestthrombocytopenia and less neurotoxicity than other vinca alkaloids.There is therefore a need to increase the inhibitory efficacy ofanti-tumour vinca alkaloids against tumour growth and also to provide ameans for the use of lower dosages of anti-tumour vinca alkaloids toreduce the potential of adverse toxic side effects to the patient.

Preferences:

Preferred anti-tumour vinca alkaloids for use in accordance with theinvention include vindesine, vinvesir, vinblastine, vincristine andvinorelbine. Particularly preferred anti-tumour Arica alkaloids for usein accordance with the invention include vinblastine, vincristine andvinorelbine referred to above. Vinblastine is commercially available forexample as the sulphate salt for injection from Eli Lilly and Co underthe trade name Velban, and may be prepared for example as described inGerman patent specification No. 2124023 or by processes analogousthereto. Vincristine is commercially available for example as thesulphate salt for injection from Eli Lilly and Co under the trade nameOncovin and may be prepared for example as described in the above Germanpatent specification No. 2124023 or by processes analogous thereto.Vincristine is also available as a liposomal formulation under the nameOnco-TCS™. Vinorelbine is commercially available for example as thetartrate salt for injection from Glaxo Wellcome under the trade nameNavelbine and may be prepared for example as described in U.S. Pat. No.4,307,100, or by processes analogous thereto. Other anti-tumour vincaalkaloids may be prepared in conventional manner for example byprocesses analogous to those described above for vinoblastine,vincristine and vinorelbine.

Another preferred vinca alkaloid is vindesine. Vindesine is a syntheticderivative of the dimeric catharanthus alkaloid vinblastine, isavailable from Lilly under the tradename Eldisine and from Shionogiunder the tradename Fildesin. Details of the synthesis of Vindesine aredescribed in Lilly patent DE2415980 (1974) and by C. J. Burnett et al.,J. Med. Chem. 21, 88 (1978).

Specific Embodiments:

In one embodiment, the vinca alkaloid compound is selected fromvinoblastine, vincristine and vinorelbine. In another embodiment, thevinca alkaloid compound is vinoblastine.

Posology:

The anti-tumour vinca alkaloid is advantageously administered in adosage of 2 to 30 mg or square meter (mg/m²) of body surface area,particularly for vinblastine in a dosage of about 3 to 12 mg/m², forvincristine in a dosage of about 1 to 2 mg/m², and for vinorelbine indosage of about 10 to 30 mg/m² per course of treatment. These dosagesmay be administered for example once, twice or more per course oftreatment, which may be repeated for example every 1, 14, 21 or 28 days.

8. Taxanes

Definition:

The term “taxane compound” as used herein refers to taxane compounds oranalogues of taxane compounds as described herein, including the ionic,salt, solvate, isomers, tautomers, N-oxides, ester, prodrugs, isotopesand protected forms thereof (preferably the salts or tautomers orisomers or N-oxides or solvates thereof, and more preferably, the saltsor tautomers or N-oxides or solvates thereof), as described above.

Technical Background:

The taxanes are a class of compounds having the taxane ring system andrelated to or derived from extracts from certain species of yew (Taxus)trees. These compounds have been found to have activity against tumourcell growth and certain compounds in this class have been used in theclinic for the treatment of various cancers. Thus, for example,paclitaxel is a diterpene isolated from the bark of the yew tree, Taxusbrevifolia, and can be produced by partial synthesis from10-acetylbacctin, a precursor obtained from yew needles and twigs or bytotal synthesis, see Holton et al, J. Am. Chem. Soc. 116; 1597-1601(1994) and Nicholau et al, Nature 367:630 (1994). Paclitaxel has shownanti-neoplastic activity and more recently it has been established thatits antitumour activity is due to the promotion of microtubulepolymerisation, Kumar N. J., Biol. Chem. 256: 1035-1041 (1981); Rowinskyet al, J. Natl. Cancer Inst. 82: 1247-1259 (1990); and Schiff et al,Nature 277: 655-667 (1979). Paclitaxel has now demonstrated efficacy inseveral human tumours in clinical trials, McGuire et al, Ann. Int. Med.,111:273-279 (1989); Holmes at al, J. Natl. Cancer Inst. 83: 1797-1805(1991); Kohn et al J. Natl. Cancer Inst. 86: 18-24 (1994); and Kohn etal, American Society for Clinical Oncology, 12 (1993). Paclitaxel hasfor example been used for the treatment of ovarian cancer and alsobreast cancer.

Another taxane compound which has been used in the clinic is docetaxelwhich has been shown to have particular efficacy in the treatment ofadvanced breast cancer. Docetaxel has shown a better solubility inexcipient systems than paclitaxel, therefore increasing the ease withwhich it can be handled and used in pharmaceutical compositions.

Biological Activity:

The taxane compounds of the combinations of the invention are tubulintargeting agents and have activity against various cancers.

Problems:

Clinical use of taxanes has demonstrated a narrow therapeutic index withmany patients unable to tolerate the side effects associated with itsuse. There is therefore a need to increase the inhibitory efficacy oftaxane compounds against tumour growth and also to provide a means forthe use of lower dosages of taxane compounds to reduce the potential ofadverse toxic side effects to the patient.

Preferences:

Preferred taxane compounds for use in accordance with the inventioninclude paclitaxel or docetaxel referred to herein. Paclitaxel isavailable commercially for example under the trade name Taxol fromBristol Myers Squibb and docetaxel is available commercially under thetrade name Taxotere from Rhone-Poulenc Rorer. Both compounds and othertaxane compounds may be prepared in conventional manner for example asdescribed in EP 253738, EP 253739 and WO 92/09589 or by processesanalogous thereto.

Specific Embodiments:

In one embodiment, the taxane compound is paclitaxel. In anotherembodiment, the taxane compound is docetaxel.

Posology:

The taxane compound is advantageously administered in a dosage of 50 to400 mg per square meter (mg/m²) of body surface area, for example 75 to250 mg/m², particularly for paclitaxel in a dosage of about 175 to 250mg/m² and for docetaxel in about 75 to 150 mg/m² per course oftreatment. These dosages may be administered for example once, twice ormore per course of treatment, which may be repeated for example every 7,14, 21 or 28 days.

9. Epothilones

Definition:

As used herein, the term “epothilone” is used to define a class ofcytotoxic macrolides with a similar mechanism of action to paclitaxelbut with the potential advantage of activity in taxane-resistantsettings in preclinical models. The epothilones ixabepilone, patupilone,BMS-310705, KOS-862 and ZK-EPO are in early clinical trials for cancertreatment. Phase I studies have shown that dose-limiting toxicities ofepothilones are generally neurotoxicity and neutropoenia althoughinitial studies with patupilone indicated that diarrhoea was doselimiting. Neuropathy induced by ixabepilone may be schedule dependent.Response rates in taxane-refractory metastatic breast cancer arerelatively modest, but ixabepilone and patupilone have shown promisingefficacy in hormone-refractory metastatic prostate cancer and intaxane-refractory ovarian cancer.

Technical Background:

Epothilones A and B were originally isolated as anti-fungal fermentationproducts of the myxobacteria Sorangium cellulosum. Shortly thereafterthese agents were demonstrated to stabilize microtubules and inducemitotic arrest. Epothilones are known to compete with Taxol formicrotubule binding. Though their cytotoxic activity relies on the samemechanism as that of the taxanes, the epothilones have a couple of keyadvantages. Firstly they are not substrates for the multi-drugresistance pump P-gylycoprotein. Secondly they are easier both toproduce (because of their bacterial origin) and to manipulate. Chemicalsyntheses, either total or partial, of these molecules and their analogsallows for modification to enhance their efficacy Mani et al. AnticancerDrugs 2004; 15(6):553-8). Several epothilones or epothilone-derivativeshave been shown effective against cell lines and tumor xenografts andare now in clinical trials (Goodin et al. J Clin Oncol 2004; 22(10):2015-25). An unexpected source for the identification of microtubulestabilizing agents has been marine organisms. Laulimalide andisolaulimalide are natural products of the marine sponge Cacospongiamycofijiensis with strong Taxol-like activity, even against P-gpexpressing cell lines. Eluetherobin, similar in both respects, is aproduct of the Eleutherobia species of soft coral.

Biological Activity:

Formation of microtubules involves polymerization of heterodimericα/β-tubulin subunits with multiple isoforms of both α- and β-tubulinpresent in human cells. Intact microtubule function is required forformation and functioning of the mitotic spindle, and cells treated withagents that bind either tubulin subunits or polymerized microtubulesexhibit alterations in spindle formation, as well as arrest at the G2/Mphase of the cell cycle, which is associated with induction ofapoptosis. Compounds that target microtubules are potent cytotoxicagents, exemplified by the convergent evolution of microtubule-targetingcompounds by a variety of plant and marine species. Published studies ofthree epothilones in current clinical development, epothilone B,aza-epothilone B, and desoxyepothilone B, indicate that these compoundsexhibit broad spectrum antitumor activity in cell culture models and inxenografts. Furthermore, epothilones are generally more cytotoxic thanpaclitaxel in cell culture studies, with IC₅₀ values in the sub- or lownanomolar range in a variety of tumor cell lines (Bollag et al. CancerRes 55:2325-2333, 1995; Lee et al. Clin Cancer Res 7:1429-1437, 2001;Chou et al. Proc Natl Acad Sci U S A 95:9642-9647, 1998; Newman et al.Cancer Chemother Pharmacol 48:319-326, 2001). Preclinical studies alsodemonstrated important differences with regard to drug resistancemechanisms between epothilones and taxanes. In particular,overexpression of P-glycoprotein minimally affects the cytotoxicity ofepothilone B, aza-epothilone B, and desoxyepothilones in cell culturemodels. Comparison of the cytotoxic effects of epothilone B,aza-epothilone B, and desoxyepothilone B amongP-glycoprotein-overexpressing cell lines suggests that desoxyepothiloneB is least affected, whereas aza-epothilone B is most affected byP-glycoprotein expression. However, it should be noted that differencesamong the IC₅₀s of these compounds in P-glycoprotein-overexpressing celllines are small compared with the differences between these values andIC₅₀s for paclitaxel in these cell lines. Although the significance ofP-glycoprotein expression in clinical resistance to taxanes remainsuncertain, these results suggest that epothilones may be more activethan taxanes in patients with malignancies characterized by high levelsof P-glycoprotein expression. In vivo studies indicate that epothilonesare active in paclitaxel-sensitive and -resistant tumor models using avariety of schedules. When administered intravenously to mice usingintermittent daily or weekly schedules, aza-epothilone B is highlyactive in ovarian, colon, and breast xenografts and induces cures in anovarian xenograft model (Pat-7) that is resistant to paclitaxel.Notably, unlike paclitaxel, aza-epothilone B is effective whenadministered orally in preclinical models. This phenomenon likelyrelates to the expression of P-glycoprotein in intestinal mucosa,resulting in poor absorption of paclitaxel but not epothilones.

Problems:

Sensory Neuropathy has been Documented with Epothilones

Preferences:

Existing structure-activity data provide some insight into theinteraction between epothilones and microtubules. Results from severalgroups indicate that modifications at or near the C12-13 epoxide canaffect microtubule-stabilizing activity (Wartmann and Altmann, Curr MedChem Anti-Canc Agents 2:123-148, 2002). For example, addition of amethyl group to epothilone A at position C12 yields epothilone B, whichis approximately twice as potent as epothilone A or paclitaxel ininducing tubulin polymerization in vitro (Kowalski et al. J Biol Chem272: 2534-2541, 1997; Nicolaou et al. Nature 387:268-272, 1997, abstr428). In addition, it is clear that an epoxide at C12-13 is not requiredfor microtubule-binding, because desoxyepothilone B (also known asepothilone D or KOS-862) lacks the C12-13 epoxide and is a more potentmicrotubule stabilizer in vitro than epothilone A or B. Less data areavailable regarding the effects of modifying other regions ofepothilone. Despite attempts to improve microtubule binding by alteringthe C9-C12 region (on the basis of molecular modeling), alterations inthis area resulted in loss of cytotoxic activity. By contrast,replacement of the lactone oxygen of epothilone B with a lactam(aza-epothilone B, also known as BMS-247550) does not impairmicrotubule-polymerizing activity or cytotoxicity. Although a variety ofother epothilone analogs have been synthesized, it should be noted thatincreasing microtubule-stabilizing activity does not always result inincreased cytotoxicity, presumably because of the importance of othervariables such as cellular accumulation and metabolic stability(Wartmann and Altmann, Curr Med Chem Anti-Canc Agents 2:123-148, 2002).Indeed, replacement of the methyl group at C12 position ofdesoxyepothilone B with a propanol group results in a compound that isas effective as desoxyepothilone B against the leukemic cell lineCCRF-CEM but is significantly less active against aP-glycoprotein-overexpressing subline (IC₅₀ of 17 nmol/L fordesoxyepothilone B v 167 nmol/L for the propanol derivative) (Chou etal. Proc Natl Acad Sci U S A 95:9642-9647, 1998). Additionalmodifications of naturally occurring epothilones have been made in aneffort to improve solubility, such as BMS-310705, which is aC-21-substituted derivative of epothilone B (Lee et al. Proc Am AssocCancer Res 43′a3928, 2002).

Specific Embodiments:

In one embodiment, the epothilone compound is BMS-247550. In anotherembodiment, the epothilone compound is Desoxyepothilone and in anotherembodiment the epothilone compound is BMS-310705

Posology:

BMS-247550 is dosed either 40 mg/m² over 3 hours every 21 days or 6mg/m² administered over 1 hour daily times 5 days every 3 weeks. Becauseof the frequency of mucositis and neutropenia in the first 18 patientson the single-dose every-3-week schedule, the dose was reduced to 32mg/m². EP0906 is dosed either at 2.5 mg/m² weekly for 3 weeks followedby 1 week of rest in one trial, and 6 mg/m² once every 3 weeks. KOS-862is scheduled at either a single dose every 3 weeks, a daily dose times 3every 3 weeks, a fixed rate dose every 3 weeks, and a weekly dose for 3weeks with 1 week rest.

10. Platinum Compounds

Definition:

The term “platinum compounds” as used herein refers to any tumour cellgrowth inhibiting platinum compound including platinum coordinationcompounds, compounds which provide platinum in the form of an ion andanalogues of platinum compounds as described herein, including theionic, salt, solvate, isomers, tautomers, N-oxides, ester, prodrugs,isotopes and protected forms thereof (preferably the salts or tautomersor isomers or N-oxides or solvates thereof, and more preferably, thesalts or tautomers or N-oxides or solvates thereof), as described above.

Technical Background:

In the chemotherapeutic treatment of cancers, cisplatin(cis-diaminodichloroplatinum (II)) has been used successfully for manyyears in the treatment of various human solid malignant tumours forexample testicular cancer, ovarian cancer and cancers of the head andneck, bladder, oesophagus and lung.

More recently, other diamino-platinum complexes, for example carboplatin(diamino(I,1-cyclobutane-dicarboxylato)platinum (II)), have also shownefficacy as chemotherapeutic agents in the treatment of various humansolid malignant tumours, carboplatin being approved for the treatment ofovarian cancer. A further antitumour platinum compound is oxaliplatin(L-OHP), a third generation diamino-cyclohexane platinum-based cytotoxicdrug, which has the chemical name(1,2-diaminocyclohexane)oxalato-platinum (II). Oxaliplatin is used, forexample, for the treatment of metastatic colorectal cancer, based on itslack of renal toxicity and higher efficacy in preclinical models ofcancer in comparison to cisplatin.

Biological Activity:

The platinum compounds of the combinations of the invention haveactivity against various cancers.

Problems:

Although cisplatin and other platinum compounds have been widely used aschemotherapeutic agents in humans, they are not therapeuticallyeffective in all patients or against all types of tumours. Moreover,such compounds need to be administered at relatively high dosage levelswhich can lead to toxicity problems such as kidney damage. Also, andespecially with cisplatin, the compounds cause nausea and vomiting inpatients to a varying extent, as well as leucopenia, anemia andthrombocytopenia. There is therefore a need to increase efficacy andalso to provide a means for the use of lower dosages to reduce thepotential of adverse toxic side effects to the patient.

Preferences:

Preferred platinum compounds for use in accordance with the inventioninclude cisplatin, carboplatin and oxaliplatin. Other platinum compoundsinclude chloro(diethylenediamino)-platinum (II) chloride;dichloro(ethylenediamine)-platinum (II); spiroplatin; iproplatin;diamino(2-ethylmalonato)platinum (II);(1,2-diaminocyclohexane)malonatoplatinum (II);(4-carboxyphthalo)-(1,2-diaminocyclohexane)platinum (II);(1,2-diaminocyclohexane)-(isocitrato)platinum (II);(1,2-diaminocyclohexane)-cis-(pyruvato)platinum (II); onnaplatin; andtetraplatin. Cisplatin is commercially available for example under thetrade name Platinol from Bristol-Myers Squibb Corporation as a powderfor constitution with water, sterile saline or other suitable vehicle.Cisplatin may also be prepared for example as described by G. B.Kauffman and D. O. Cowan, Inorg. Synth. 7, 239 (1963), or by processesanalogous thereto. Carboplatin is commercially available for examplefrom Bristol-Myers Squibb Corporation under the trade name Paraplatin,or may be prepared for example as described in U.S. Pat. No. 4,140,707,or by processes analogous thereto. Oxaliplatin is commercially availablefor example from Sanofi-Synthelabo Inc under the trade name Eloxatin, ormay be prepared for example as described in U.S. Pat. No. 4,169,846, orby processes analogous thereto. Other platinum compounds and theirpharmaceutical compositions are commercially available and/or can beprepared by conventional techniques.

Specific Embodiments:

In one embodiment, the platinum compound is selected fromchloro(diethylenediamino)-platinum (II) chloride;dichloro(ethylenediamine)-platinum (II); spiroplatin; iproplatin;diamino(2-ethylmalonato)platinum (II);(1,2-diaminocyclohexane)malonatoplatinum (II);(4-carboxyphthalo)-(1,2-diaminocyclohexane)platinum (II);(1,2-diaminocyclohexane)-(isocitrato)platinum (II);(1,2-diaminocyclohexane)-cis-(pyruvato)platinum (II); onnaplatin;tetraplatin, cisplatin, carboplatin and oxaliplatin. In anotherembodiment, the platinum compound is a platinum compound other thancisplatin, for example a platinum compound such aschloro(diethylenediamino)-platinum (II) chloride;dichloro(ethylenediamine)-platinum (II); spiroplatin; iproplatin;diamino(2-ethylmalonato)platinum (II);(1,2-diaminocyclohexane)malonatoplatinum (II);(4-carboxyphthalo)-(1,2-diaminocyclohexane)platinum (II);(1,2-diaminocyclohexane)-(isocitrato)platinum (II);(1,2-diaminocyclohexane)-cis-(pyruvato)platinum (II); onnaplatin;tetraplatin, carboplatin or oxaliplatin, preferably selected fromcarboplatin and oxaliplatin.

Posology:

The platinum coordination compound is advantageously administered in adosage of 1 to 500 mg per square meter (mg/m²) of body surface area, forexample 50 to 400 mg/m² particularly for cisplatin in a dosage of about75 mg/m², for carboplatin in about 300 mg/m² and for oxaliplatin inabout 50-100 mg/m². These dosages may be administered for example once,twice or more per course of treatment, which may be repeated for exampleevery 7, 14, 21 or 28 days.

11. Topoisomerase 2 Inhibitors

Definition:

The term “topoisomerase 2 inhibitor” as used herein refers totopoisomerase 2 inhibitor or analogues of topoisomerase 2 inhibitor asdescribed above, including the ionic, salt, solvate, isomers, tautomers,N-oxides, ester, prodrugs, isotopes and protected forms thereof(preferably the salts or tautomers or isomers or N-oxides or solvatesthereof, and more preferably, the salts or tautomers or N-oxides orsolvates thereof), as described above.

Technical Background:

An important class of anticancer drugs are the inhibitors of the enzymetopoisomerase 2 which causes double-strand breaks to release stressbuild-up during DNA transcription and translation. Compounds thatinhibit the function of this enzyme are therefore cytotoxic and usefulas anti-cancer agents.

Among the topoisomerase 2 inhibitors which have been developed and usedin cancer chemotherapy are the podophyllotoxins. These drugs act by amechanism of action which involves the induction of DNA strand breaks byan interaction with DNA topoisomerase 2 or the formation of freeradicals. Podophyllotoxin, which is extracted from the mandrake plant,is the parent compound from which two glycosides have been developedwhich show significant therapeutic activity in several human neoplasms,including pediatric leukemia, small cell carcinomas of the lung,testicular tumours, Hodgkin's disease, and large cell lymphomas. Thesederivatives are etoposide (VP-16), which has the chemical name4′-demethylepipodophyllotoxin9-[4,6-O-(R)-ethylidene-β-D-glucopyranoside], and teniposide (VM-26),which has the chemical name 4′-demethylepipodophyllotoxin9-[4,6-O-(R)-2-thenylidene-β-D-glucopyranoside].

Both etoposide and teniposide, however, suffer from certain toxicside-effects especially myelosuppression. Another important class oftopoisomerase 2 inhibitors are the anthracycline derivatives which areimportant anti-tumour agents and comprise antibiotics obtained from thefungus Streptomyces peuticus var. caesius and their derivatives,characterized by having a tetracycline ring structure with an unusualsugar, daunosamine, attached by a glycosidic linkage. Among thesecompounds, the most widely used include daunorubicin, which has thechemical name7-(3-amino-2,3,6-trideoxy-L-lyxohexosyloxy)-9-acetyl-7,8,9,10-tetrahydro-6,9,11-trihydroxy-4-methoxy-5,12-naphthacenequinone,doxorubicin, which has the chemical name10-[(3-amino-2,3,6-trideoxy-α-L-lyxohexopyranosyl)oxy]-7,8,9,10-tetrahydro-6,8,11-trihydroxy-8-(hydroxylacetyl)-I-methoxy-5,12-naphthacenedione,and idarubicin, which has the chemical name9-acetyl-[(3-amino-2,3,6-trideoxy-α-L-lyxohexopyranosyl)oxy]-7,8,9,10-tetrahydro-6,9,11-trihydroxy-5,12-naphthacenedione.

Daunorubicin and idarubicin have been used primarily for the treatmentof acute leukaemias whereas doxorubicin displays broader activityagainst human neoplasms, including a variety of solid tumoursparticularly breast cancer. Another anthracycline derivatives which isuseful in cancer chemotherapy is epirubicin. Epirubicin, which has thechemical name(8S-cis)-10-[(3-amino-2,3,6-trideoxy-α-L-arabino-hexopyranosyl)oxy]-7,8,9,10-tetrahydro-6,8,11-trihydroxy-8-(hydroxyacetyl)-1-methoxy-5,12-naphthacenedione,is a doxorubicin analog having a catabolic pathway that involvesglucuronidation, by uridine diphosphate-glucuronosyl transferase in theliver (unlike that for doxorubicin), which is believed to account forits shorter half-life and reduced cardiotoxicity. The compound has beenused for the treatment of various cancers including cervical cancer,endometrial cancer, advanced breast cancer and carcinoma of the bladderbut suffers from the side-effects of myelosuppression andcardiotoxicity. The latter side-effect is typical of anthracyclinederivatives which generally display a serious cardiomyopathy at higherdoses, which limits the doses at which these compounds can beadministered. A further type of topoisomerase 2 inhibitor is representedby mitoxantrone, which has the chemical name1,4-dihydroxy-5,8-bis[[2-[(2-hydroxyethyl)amino]ethyl]amino]-9,10-anthracenedione,and is used for the treatment of multiple sclerosis, non-Hodgkin'slymphoma, acute myelogenous leukaemia, and breast, prostate and livertumours. Others include losoxantrone and actinomycin D.

Side-effects from administration of mitoxantrone includemyelosuppression, nausea, vomiting, stomatitis, alopecia but lesscardiotoxicity than anthracyclines.

Biological Activity:

The topoisomerase 2 inhibitors of the combinations of the invention haveactivity against various cancers as described above.

Problems:

This class of cytotoxic compound is associated with side effects, asmentioned above. Thus, there is a need to provide a means for the use oflower dosages to reduce the potential of adverse toxic side effects tothe patient.

Preferences:

Preferred topoisomerase 2 inhibitor compounds for use in accordance withthe invention include anthracycline derivatives, mitoxantrone andpodophyllotoxin derivatives as defined to herein.

Preferred anti-tumour anthracycline derivatives for use in accordancewith the invention include daunorubicin, doxorubicin, idarubicin andepirubicin referred to above. Daunorubicin is commercially available forexample as the hydrochloride salt from Bedford Laboratories under thetrade name Cerubidine, or may be prepared for example as described inU.S. Pat. No. 4,020,270, or by processes analogous thereto. Doxorubicinis commercially available for example from Pharmacia and Upjohn Co underthe trade name Adriamycin, or may be prepared for example as describedin U.S. Pat. No. 3,803,124, or by processes analogous thereto.Doxorubicin derivatives include pegylated doxorubicin hydrochloride andliposome-encapsulated doxorubicin citrate. Pegylated doxorubicinhydrochloride is commercially available from Schering-PloughPharmaceuticals under the trade name Caeylx; liposome-encapsulateddoxorubicin citrate is commercially available for example from ElanCorporation under the trade name Myocet. Idarubicin is commerciallyavailable for example as the hydrochloride salt from Pharmacia & Upjohnunder the trade name Idamycin, or may be prepared for example asdescribed in U.S. Pat. No. 4,046,878, or by processes analogous thereto.Epirubicin is commercially available for example from Pharmacia andUpjohn Co under the trade name Pharmorubicin, or may be prepared forexample as described in U.S. Pat. No. 4,058,519, or by processesanalogous thereto. Mitoxantrone is commercially available for examplefrom OSI Pharmaceuticals, under the trade name Novantrone, or may beprepared for example as described in U.S. Pat. No. 4,197,249, or byprocesses analogous thereto.

Other anti-tumour anthracycline derivatives may be prepared inconventional manner for example by processes analogous to thosedescribed above for the specific anthracycline derivatives.

Preferred anti-tumour anti-tumour podophyllotoxin derivatives for use inaccordance with the invention include etoposide and teniposide referredto above. Etoposide is commercially available for example fromBristol-Myers Squibb Co under the trade name VePesid, or may be preparedfor example as described in European patent specification No 111058, orby processes analogous thereto. Teniposide is commercially available forexample from Bristol-Myers Squibb Co under the trade name Vumon, or maybe prepared for example as described in PCT patent specification No. WO93/02094, or by processes analogous thereto. Other anti-tumourpodophyllotoxin derivatives may be prepared in conventional manner forexample by processes analogous to those described above for etoposideand teniposide.

Specific Embodiments:

In one embodiment, the topoisomerase 2 inhibitor is an anthracyclinederivative, mitoxantrone or a podophyllotoxin derivative. In anotherembodiment, the topoisomerase 2 inhibitor is selected from daunorubicin,doxorubicin, idarubicin and epirubicin. In a further embodiment, thetopoisomerase 2 inhibitor is selected from etoposide and teniposide.Thus, in a preferred embodiment, the topoisomerase 2 inhibitor isetoposide. In another embodiment, the topoisomerase 2 inhibitor is ananthracycline derivative other than doxorubicin, for example atopoisomerase 2 inhibitor such as daunorubicin, idarubicin andepirubicin.

Posology:

The anti-tumour anthracycline derivative is advantageously administeredin a dosage of 10 to 150 mg per square meter (mg/m²) of body surfacearea, for example 15 to 60 mg/m², particularly for doxorubicin in adosage of about 40 to 75 mg/m², for daunorubicln in a dosage of about 25to 45 mg/m², for idarubicin in a dosage of about 10 to 15 mg/m² and forepirubicin in a dosage of about 100-120 mg/m².

Mitoxantrone is advantageously administered in a dosage of about 12 to14 mg/m² as a short intravenous infusion about every 21 days.

The anti-tumour podophyllotoxin derivative is advantageouslyadministered in a dosage of 30 to 300 mg/m² of body surface area, forexample 50 to 250 mg/m particularly for etoposide in a dosage of about35 to 100 mg/m, and for teniposide in about 50 to 250 mg/m².

The dosages noted above may generally be administered for example once,twice or more per course of treatment, which may be repeated for exampleevery 7, 14, 21 or 28 days.

12. Alkylating Agents

Definition:

The term “alkylating agent” or “alkylating agents” as used herein refersto alkylating agents or analogues of alkylating agents as describedherein, including the ionic, salt, solvate, isomers, tautomers,N-oxides, ester, prodrugs, isotopes and protected forms thereof(preferably the salts or tautomers or isomers or N-oxides or solvatesthereof, and more preferably, the salts or tautomers or N-oxides orsolvates thereof), as described above.

Technical Background:

Alkylating agents used in cancer chemotherapy encompass a diverse groupof chemicals that have the common feature that they have the capacity tocontribute, under physiological conditions, alkyl groups to biologicallyvital macromolecules such as DNA. With most of the more important agentssuch as the nitrogen mustards and the nitrosoureas, the activealkylating moieties are generated in vivo after complex degradativereactions, some of which are enzymatic. The most importantpharmacological actions of the alkylating agents are those that disturbthe fundamental mechanisms concerned with cell proliferation, inparticular DNA synthesis and cell division. The capacity of alkylatingagents to interfere with DNA function and integrity in rapidlyproliferating tissues provides the basis for their therapeuticapplications and for many of their toxic properties. Alkylating agentsas a class have therefore been investigated for their anti-tumouractivity and certain of these compounds have been widely used inanti-cancer therapy although they tend to have in common a propensity tocause dose-limiting toxicity to bone marrow elements and to a lesserextent the intestinal mucosa.

Among the alkylating agents, the nitrogen mustards represent animportant group of anti-tumour compounds which are characterised by thepresence of a bis-(2-chloroethyl) grouping and include cyclophosphamide,which has the chemical name2-[bis(2-chloroethyl)amino]tetrahydro-2H-1,3,2-oxazaphospholine oxide,and chlorambucil, which has the chemical name4-[bis(2-chloroethyl)amino]-benzenebutoic acid. Cyclophosphamide has abroad spectrum of clinical activity and is used as a component of manyeffective drug combinations for malignant lymphomas, Hodgkin's disease,Burkitt's lymphoma and in adjuvant therapy for treating breast cancer.

Ifosfamide (a.k.a. Ifosphamide) is a structural analogue ofcyclophosphamide and its mechanism of action is presumed to beidentical. It has the chemical name3-(2-chloroethyl)-2-[(2-chloroethyl)amino]tetrahydro-2H-1,3,2-oxazaphosphorin-2-oxide,and is used for the treatment of cervical cancer, sarcoma, andtesticular cancer but may have severe urotoxic effects. Chlorambucil hasbeen used for treating chronic leukocytic leukaemia and malignantlymphomas including lymphosarcoma.

Another important class of alkylating agents are the nitrosoureas whichare characterised by the capacity to undergo spontaneous non-enzymaticdegradation with the formation of the 2-chloroethyl carbonium ion.Examples of such nitrosourea compounds include carmustine (BCNU) whichhas the chemical name 1,3-bis(2-chloroethyl)-I-nitrosourea, andlomustine (CCNU) which has the chemical name1-(2-chloroethyl)cyclohexyl-I-nitrosourea. Carmustine and lomustine eachhave an important therapeutic role in the treatment of brain tumours andgastrointestinal neoplasms although these compounds cause profound,cumulative myelosuppression that restricts their therapeutic value.

Another class of alkylating agent is represented by the bifunctionalalkylating agents having a bis-alkanesulfonate group and represented bythe compound busulfan which has the chemical name 1,4-butanedioldimethanesulfonate, and is used for the treatment of chronic myelogenous(myeloid, myelocytic or granulocytic) leukaemia. However, it can inducesevere bone marrow failure resulting in severe pancytopenia.

Another class of alkylating agent are the aziridine compounds containinga three-membered nitrogen-containing ring which act as anti-tumouragents by binding to DNA, leading to cross-linking and inhibition of DNAsynthesis and function. An example of such an agent is mitomycin, anantibiotic isolated from Streptomyces caespitosus, and having thechemical name 7-amino-9α-methoxymitosane.

Mitomycin is used to treat adenocarcinoma of stomach, pancreas, colonand breast, small cell and non-small cell lung cancer, and, incombination with radiation, head and neck cancer, side-effects includingmyelosuppression, nephrotoxicity, interstitial pneumonitis, nausea andvomiting.

Biological Activity:

One of the most important pharmacological actions of the alkylatingagent in the combinations of the invention is its ability to disturb thefundamental mechanisms concerned with cell proliferation as hereinbefore defined. This capacity to interfere with DNA function andintegrity in rapidly proliferating tissues provides the basis for theirtherapeutic application against various cancers.

Problems:

This class of cytotoxic compound is associated with side effects, asmentioned above. Thus, there is a need to provide a means for the use oflower dosages to reduce the potential of adverse toxic side effects tothe patient.

Preferences:

Preferred alkylating agents for use in accordance with the inventioninclude the nitrogen mustard compounds cyclophosphamide,ifosfamide/ifosphamide and chlorambucil and the nitrosourea compoundscarmustine and lomustine referred to above. Preferred nitrogen mustardcompounds for use in accordance with the invention includecyclophosphamide, ifosfamidenfosphamide and chlorambucil referred toabove. Cyclophosphamide is commercially available for example fromBristol-Myers Squibb Corporation under the trade name Cytoxan, or may beprepared for example as described in U.K. patent specification No.1235022, or by processes analogous thereto. Chlorambucil is commerciallyavailable for example from GlaxoSmithKline plc under the trade nameLeukeran, or may be prepared for example as described in U.S. Pat. No.3,046,301, or by processes analogous thereto. Ifosfamide/ifosphamide iscommercially available for example from Baxter Oncology under the tradename Mitoxana, or may be prepared for example as described in U.S. Pat.No. 3,732,340, or by processes analogous thereto. Preferred nitrosoureacompounds for use in accordance with the invention include carmustineand lomustine referred to above. Carmustine is commercially availablefor example from Bristol-Myers Squibb Corporation under the trade nameBiCNU, or may be prepared for example as described in European patentspecification No. 902015, or by processes analogous thereto. Lomustineis commercially available for example from Bristol-Myers SquibbCorporation under the trade name CeeNU, or may be prepared for exampleas described in U.S. Pat. No. 4,377,687, or by processes analogousthereto. Busulfan is commercially available for example fromGlaxoSmithKline plc under the trade name Myleran, or may be prepared forexample as described in U.S. Pat. No. 2,917,432, or by processesanalogous thereto. Mitomycin is commercially available for example fromBristol-Myers Squibb Corporation under the trade name Mutamycin. Othersinclude estramustine, mechlorethamine, melphalan,bischloroethylnitrosurea, cyclohexylchloroethylnitrosurea,methylcyclohexylchloroethylnitrosurea, nimustine, procarbazine,dacarbazine, temozoiimide and thiotepa.

Specific Embodiments:

In one embodiment, the alkylating agent is a nitrogen mustard compoundselected from cyclophosphamide, ifosfamide/ifosphamide and chlorambucil.In another embodiment, the alkylating agent is a nitrosourea selectedfrom carmustine and lomustine. The alkylating agents further includeBusulfan. In one embodiment, the alkylating agents are as herein beforedefined other than mitomycin C or cyclophosphamide.

Posology:

The nitrogen mustard or nitrosourea alkylating agent is advantageouslyadministered in a dosage of 100 to 2500 mg per square meter (mg/m²) ofbody surface area, for example 120 to 500 mg/m², particularly forcyclophosphamide in a dosage of about 100 to 500 mg/m², forifosfamide/ifosphamide in a dosage of 500-2600 mg/m², for chlorambucilin a dosage of about 0.1 to 0.2 mg/kg, for carmustine in a dosage ofabout 150 to 200 mg/m² and for lomustine in a dosage of about 100 to 150mg/m². For bis-alkanesulfonate compounds such

Aziridine alkylating agents such as mitomycin can be administered forexample in a dosage of 15 to 25 mg/m² preferably about 20 mg/m².

The dosages noted above may be administered for example once, twice ormore per course of treatment, which may be repeated for example every 7,14, 21 or 28 days.

13. Signalling Inhibitors

Definition:

The term “signalling inhibitor” as used herein refers to signallinginhibitors or analogues of signalling inhibitors as described herein,including the ionic, salt, solvate, isomers, tautomers, N-oxides, ester,prodrugs, isotopes and protected forms thereof (preferably the salts ortautomers or isomers or N-oxides or solvates thereof, and morepreferably, the salts or tautomers or N-oxides or solvates thereof), asdescribed above.

Technical Background:

A malignant tumour is the product of uncontrolled cell proliferation.Cell growth is controlled by a delicate balance between growth-promotingand growth-inhibiting factors. In normal tissue the production andactivity of these factors results in differentiated cells growing in acontrolled and regulated manner that maintains the normal integrity andfunctioning of the organ. The malignant cell has evaded this control;the natural balance is disturbed (via a variety of mechanisms) andunregulated, aberrant cell growth occurs.

One driver for growth is the epidermal growth factor (EGF), and thereceptor for EGF (EGFR) has been implicated in the development andprogression of a number of human solid tumours including those of thelung, breast, prostate, colon, ovary, head and neck. EGFR is a member ofa family of four receptors, namely EGFR (HER1 or ErbB1), ErbB2(HER2/neu), ErbB3 (HER3), and ErbB4 (HER4). These receptors are largeproteins that reside in the cell membrane, each having a specificexternal ligand binding domain, a transmembrane domain and an internaldomain which has tyrosine kinase enzyme activity. When EGF attaches toEGFR, it activates the tyrosine kinase, triggering reactions that causethe cells to grow and multiply. EGFR is found at abnormally high levelson the surface of many types of cancer cells, which may divideexcessively in the presence of EGF. Inhibition of EGRF activity hastherefore been a target for chemotherapeutic research in the treatmentof cancer. Such inhibition can be effected by direct Interference withthe target EGRF on the cell surface, for example by the use ofantibodies, or by inhibiting the subsequent tyrosine kinase activity.

Examples of antibodies which target EGRF are the monoclonal antibodiestrastuzumab and cetuximab. Amplification of the human epidermal growthfactor receptor 2 protein (HER 2) in primary breast carcinomas has beenshown to correlate with a poor clinical prognosis for certain patients.Trastuzumab is a highly purified recombinant DNA-derived humanizedmonoclonal IgG1 kappa antibody that binds with high affinity andspecificity to the extracellular domain of the HER2 receptor. In vitroand in vivo preclinical studies have shown that administration oftrastuzumab alone or in combination with paclitaxel or carboplatinsignificantly inhibits the growth of breast tumour-derived cell linesthat over-express the HER2 gene product. In clinical studies trastuzumabhas been shown to have clinical activity in the treatment of breastcancer. The most common adverse effects of trastuzumab are fever andchills, pain, asthenia, nausea, vomiting, diarrhea, headache, dyspnea,rhinitis, and insomnia. Trastuzumab has been approved for the treatmentof metastatic breast cancer involving over-expression of the HER2protein in patients who have received one or more chemotherapy regimes.

Cetuximab has been used for the treatment of irotecan-refractorycolorectal cancer. It is also being evaluated both as a single agent andin combination with other agents for use in the treatment of a varietyof other cancers for example head and neck cancer, metastatic pancreaticcarcinoma, and non-small-cell lung cancer. The administration ofcetuximab can cause serious side effects, which may include difficultyin breathing and low blood pressure.

Examples of agents which target EGRF tyrosine kinase activity includethe tyrosine kinase inhibitors gefitinib and erlotinib. Gefitinib whichhas the chemical name4-(3-chloro-4-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline,is used for the treatment of non-small-cell lung cancer, and is alsounder development for other solid tumours that over-express EGFreceptors such as breast and colorectal cancer. It has been found thatpatients receiving gefitinib may develop interstitial lung disease thatcauses inflammation within the lung. Eye irritation has also beenobserved in patients receiving gefitinib. Erlotinib, which has thechemical nameN-(3-ethynyl-phenyl)-6,7-bis(2-methonethoxy)-4-quinazoline, has alsobeen used for the treatment of non-small-cell lung cancer, and is beingdeveloped for the treatment of various other solid tumours such aspancreatic cancer, the most common side effects being rash, loss ofappetite and fatigue; a more serious side effect which has been reportedis interstitial lung disease.

Another growth factor which has received attention as a target foranticancer research is the vascular endothelial growth factor (VEGF).VEGF is a key regulator of vasculogenesis during angiogenic processesincluding wound healing, retinopathy, psoriasis, inflammatory disorders,tumour growth and metastasis. Studies have shown that over-expression ofVEGF is strongly associated with invasion and metastasis in humanmalignant disease.

An example of an antibody that targets the VEGF antigen on the surfaceof a cell is the monoclonal antibody bevacizumab which is a recombinanthumanised monoclonal IgG1 antibody that binds to and inhibits VEGF.Bevacizumab has been used for the treatment of colorectal cancer, forexample in combination with 5-fluorouracil. Bevacizumab also beingdeveloped as a potential treatment for other solid tumours such asmetastatic breast cancer, metastatic non-small-cell lung cancer andrenal cell carcinoma. The most serious adverse events associated withbevacizumab include gastrointestinal perforations, hypertensive crises,nephrotic syndrome and congestive heart failure. Other therapeuticagents in development which target the action of VEGF at alternatepoints in the signal transduction cascade initiated by this growthfactor include sunitinib which is marketed under the trade name Sutentby Sugen/Pfizer and inhibits the kinase activity of the VEGF receptor.Sutent has demonstrated efficacy in Phase III trials in gastrointestinaltumours.

Another growth factor of importance in tumour development is theplatelet-derived growth factor (PDGF) that comprises a family of peptidegrowth factors that signal through cell surface tyrosine kinasereceptors (PDGFR) and stimulate various cellular functions includinggrowth, proliferation, and differentiation. PDGF expression has beendemonstrated in a number of different solid tumours includingglioblastomas and prostate carcinomas. The tyrosine kinase inhibitorimatinib mesylate, which has the chemical name4-[(4-methyl-1-piperazinyl)methyl]-N-[4-methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-ylpyridinyl]amino]-phenyl]benzamidemethanesulfonate, blocks activity of the Bcr-Abl oncoprotein and thecell surface tyrosine kinase receptor c-Kit, and as such is approved forthe treatment on chronic myeloid leukemia and gastrointestinal stromaltumours. Imatinib mesylate is also a potent inhibitor of PDGFR kinaseand is currently being evaluated for the treatment of chronicmyelomonocytic leukemia and glioblastoma multiforme, based upon evidencein these diseases of activating mutations in PDGFR. The most frequentlyreported drug-related adverse events were edema, nausea, vomiting,cramps and musculosketetal pain.

A further growth factor target for cancer chemotherapy is inhibition ofRaf which is a key enzyme in the chain reaction of the body's chemistrythat triggers cell growth. Abnormal activation of this pathway is acommon factor in the development of most cancers, including two-thirdsof melanomas. By blocking the action of Raf kinase, it may be possibleto reverse the progression of these tumours. One such inhibitor issorafenib (BAY 43-9006) which has the chemical name4-(4-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)phenoxy)-N2-methylpyridine-2-carboxamide.Sorafenib targets both the Raf signalling pathway to inhibit cellproliferation and the VEGFR/PDGFR signalling cascades to inhibit tumourangiogenesis. Raf kinase is a specific enzyme in the Ras pathway.Mutations in the Ras gene occur in approximately 20 percent of all humancancers, including 90 percent of pancreatic cancers, 50 percent of coloncancers and 30 percent of non-small cell lung cancers. Sorafenib isbeing investigated for the treatment of a number of cancers includingliver and kidney cancer. The most common side effects of sorafenib arepain, swelling, redness of the hands and/or feet, and also rash, fatigueand diarrhea.

Biological Activity:

The signalling inhibitors of the combinations of the invention arespecific inhibitors of cell signalling proteins as described above andhave activity against various cancers. Combinations of compounds ofFormula I with signalling inhibitors may be beneficial in the treatmentand diagnosis of many types of cancer. Combination with a molecularlytargeted agent such as a signalling inhibitor (e.g. Iressa, Avastin,herceptin, or Gleevec™) would find particular application in relation tocancers which express or have activated the relevant molecular targetsuch as EGF receptor, VEGF receptor, ErbB2, BCRabl, c-kit, PDGF.Diagnosis of such tumours could be performed using techniques known to aperson skilled in the art and as described herein such as RTPCR andFISH.

Problems:

There is a need to increase the inhibitory efficacy of signallinginhibitors against tumour growth and also to provide a means for the useof lower dosages of signaling inhibitors to reduce the potential foradverse toxic side effects to the patient.

Preferences:

Preferred signalling inhibitors for use in accordance with the inventioninclude antibodies targeting EGFR such as monoclonal antibodiestrastuzumab and cetuximab, EGFR tyrosine kinase inhibitors such asgefitinib and erlotinib, VEGF targeting antibody is bevacizumab, PDGFRinhibitor such as imatinib mesylate and Raf inhibitor such as sorafenibreferred to herein.

Preferred antibodies targeting EGFR include the monoclonal antibodiestrastuzumab and cetuximab. Trastuzumab is commercially available fromGenentech Inc under the trade name Herceptin, or may be obtained asdescribed in U.S. Pat. No. 5,821,337. Cetuximab is commerciallyavailable from Bristol-Myers Squibb Corporation under the trade nameErbitux, or may be obtained as described in PCT patent specification No.WO 96/40210.

Preferred EGFR tyrosine kinase inhibitors include gefitinib anderlotinib. Gefitinib is commercially available from AstraZeneca plcunder the trade name Iressa, or may be obtained as described in PCTpatent specification No. WO 96/33980. Erlotinib is commerciallyavailable from Pfizer Inc under the trade name Tarceva, or may beobtained as described in PCT patent specification No. WO 96/30347.

A preferred antibody targeting VEGF is bevacizumab which is commerciallyavailable from Genentech Inc under the trade name Avastin, or may beobtained as described in PCT patent specification No. WO 94/10202.

A preferred PDGFR inhibitor is imatinib mesylate which is commerciallyavailable from Novartis AG under the trade name Gleevec™ (a.k.a.Glivece), or may be obtained as described in European patentspecification No 564409.

A preferred Raf inhibitor is sorafenib which is available from Bayer AG,or may be obtained as described in PCT patent specification No. WO00/42012.

Specific Embodiments:

In one embodiment, the signalling inhibitor is gefitinib (Iressa). Inother embodiments the signalling Inhibitor is selected from trastuzumab,cetuximab, gefitinib, erlotinib, bevacizumab, imatinib mesylate andsorafenib.

Posology:

With regard to the EGFR antibodies, these are generally administered ina dosage of 1 to 500 mg per square meter (mg/m²) of body surface area,trastuzumab being advantageously administered in a dosage of 1 to 5mg/m² of body surface area, particularly 2 to 4 mg/m²; cetuxumab isadvantageously administered in a dosage of about 200 to 400 mg/m²,preferably about 250 mg/m².

With regard to the EGFR tyrosine kinase inhibitors, these are generallyadministered in a daily oral dosage of 100 to 500 mg, for examplegefitinib in a dosage of about 250 mg and erlotinib in a dosage of about150 mg.

With regard to the VEGF monoclonal antibody bevacizumab, this isgenerally administered in a dosage of about 1 to 10 mg/kg for exampleabout 5 mg/kg.

With regard to the PDGF inhibitor imatinib, this is generallyadministered in a dosage of about 400 to 800 mg per day preferably about400 mg per day.

With regard to the Raf inhibitor sorfenib, this is still underevaluation but a possible dosage is about 800 mg daily.

These dosages may be administered for example once, twice or more percourse of treatment, which may be repeated for example every 7, 14, 21or 28 days.

PKA/B Inhibitors, PKB Pathway Inhibitors and Ancillary PKB Inhibitors

Another preferred class of signaling inhibitor for use in thecombinations of the invention are PKA/B inhibitors, PKB pathwayinhibitors and ancillary PKB inhibitors.

PKB pathway inhibitors are those that inhibit the activation of PKB, theactivity of the kinase itself or modulate downstream targets, blockingthe proliferative and cell survival effects of the pathway. Targetenzymes in the pathway include phosphatidyl inositol-3 kinase (PI3K),PKB itself, mammalian target of rapamycin (MTOR), PDK-1 and p70 S6kinase and forkhead translocation. Several components of the PI3-kinase/PKB/PTEN pathway are implicated in oncogenesis. In addition togrowth factor receptor tyrosine kinases, integrin-dependent celladhesion and G-protein coupled receptors activate PI 3-kinase bothdirectly and indirectly through adaptor molecules. Functional loss ofPTEN (the most commonly mutated tumour-suppressor gene in cancer afterp53), oncogenic mutations in PI 3-kinase, amplification of PI 3-kinaseand overexpression of PKB have been established in many malignancies. Inaddition, persistent signaling through the PI 3-kinase/PKB pathway bystimulation of the Insulin-like growth factor receptor is a mechanism ofresistance to epidermal growth factor receptor inhibitors.

The discovery of non-random, somatic mutations in the gene encodingp110α in a range of human tumours suggests an oncogenic role for themutated PI 3-kinase enzyme (Samuels, et al., Science, 304 554, April2004). Mutations in p110α have since been detected in the followinghuman tumours: colon (32%), hepatocellular (36%) and endometroid andclear cell cancer (20%). p110α is now the most commonly mutated gene inbreast tumours (25-40%). Forkhead family translocations often occur inacute leukemia.

The PI 3-kinase/PKB/PTEN pathway is thus an attractive target for cancerdrug development since such agents would be expected to inhibitproliferation and surmount resistance to cytotoxic agents in cancercells. Examples of PKB pathway inhibitors include PI3K Inhibitors suchas Semaphore, SF1126 and MTOR inhibitors such as Rapamycin Analogues.RAD 001 (everolimus) from Novartis is an orally available derivative ofthe compound rapamycin. The compound is a novel macrolide, which isbeing developed as an antiproliferative drug with applications as animmunosuppressant and anticancer agent. RAD001 exerts its activity ongrowth-factor dependent proliferation of cells through its high affinityfor an intracellular receptor protein, FKBP-12. The resultingFKBP-12/RAD001 complex then binds with mTOR to inhibit downstreamsignaling events. The compound is currently in clinical development fora wide variety of oncology indications. CCI 779 (temsirolemus) fromWyeth Pharmaceuticals and AP23573 from Ariad Pharmaceuticals are alsorapamycin analogues. AP23841 and AP23573 from Ariad Pharmaceutical alsotarget mTOR. Calmodulin inhibitors from Harvard are forkheadtranslocation inhibitors. (Nature Reviews drug discovery, Exploiting thePI3K/AKT Pathway for Cancer Drug Discovery; Bryan T. Hennessy, Debra L.Smith, Prahlad T. Ram, Yiling Lu and Gordon B. Mills; December 2005,Volume 4; pages 988-1004).

Preferred PKA/B inhibitors for use as ancillary agents in thecombinations of the invention are compounds of formula (I) as definedherein. PKB pathway inhibitors for use in the combinations of theinvention include the ancillary PKB inhibitors described in more detailbelow as well as compounds of formula (I) that have protein kinase B(PKB) and/or protein kinase A (PKA) inhibiting or modulating activity(described herein). Thus, the combinations of the present invention maycomprise (or consist essentially of) two or more compounds of formula(I) as defined herein. Preferred ancillary PKB inhibitors are discussedin more detail below.

Definitions:

The term “PKA/B inhibitor” is used herein to define a compound offormula (I) which has protein kinase B (PKB) and/or protein kinase A(PKA) inhibiting or modulating activity, including the ionic, salt,solvate, isomers, tautomers, N-oxides, ester, prodrugs, isotopes andprotected forms thereof (preferably the salts or tautomers or isomers orN-oxides or solvates thereof, and more preferably, the salts ortautomers or N-oxides or solvates thereof), as described above.

The term “ancillary PKB inhibitor” is used herein to define a compoundwhich inhibits or modulates protein kinase B (PKB) and which does notconform to the structure of formula (I) as defined herein, including theionic, salt, solvate, isomers, tautomers, N-oxides, ester, prodrugs,isotopes and protected forms thereof (preferably the salts or tautomersor isomers or N-oxides or solvates thereof, and more preferably, thesalts or tautomers or N-oxides or solvates thereof), as described above.

The term “PKB pathway inhibitor” is used herein to define a compoundwhich Inhibits the activation of PKB, the activity of the kinase itselfor modulate downstream targets, blocking the proliferative and cellsurvival effects of the pathway (including one or more of the targetenzymes in the pathway as described herein, including phosphatidylinositol-3 kinase (PI3K), PKB itself, mammalian target of rapamycin(MTOR), PDK-1 and p70 S6 kinase and forkhead translocation).

Technical Background:

KRX-0401 (Perifosine/NSC 639966) is a synthetic substituted heterocyclicalkylphosphocholine that acts primarily at the cell membrane targetingsignal transduction pathways, including inhibition of PKBphosphorylation. KRX-0401 has been evaluated in phase 1 studies as apotential oral anticancer drug. Dose limiting toxicities includednausea, vomiting and fatigue. Gastrointestinal toxicities increased athigher doses. A phase II trial in refractory sarcoma is planned.

API-2/TCN is a small molecule inhibitor of PKB signaling pathway intumour cells. Phase I and II clinical trials of API-2/TCN have beenconducted on advanced tumours. API-2/TCN exhibited some side effects,which include hepatotoxicity, hypertriglyceridemia, thrombocytopenia,and hyperglycemia. Due to its severe side effects at high doses,API-2/TCN has been limited in the clinic.

RX-0201 is being developed as an AKT protein kinase inhibitor for thetreatment of solid tumours. In July 2004, a phase I trial was initiatedin patients with advanced or metastasized cancers. Data from this showedRX-0201 inhibited overexpression of Akt and suppressed cancer growth inbrain, breast, cervix, liver, lung, ovary, prostate and stomach tumours,and was well tolerated. By March 2005, US Orphan Drug status had beengranted to RX-0201 for several solid tumour types.

Enzastaurin HCl (LY317615) suppresses angiogenesis and was advanced forclinical development based upon anti-angiogenic activity. It isdescribed as a selective PKCβ inhibitor. It also has a directanti-tumour effect, and suppresses GSK3β phosphorylation.

SR-13668 is claimed to be an orally active specific AKT inhibitor thatsignificantly inhibits phospho-AKT in breast cancer cells both in vitroand in vivo. In vivo assessment in mice showed no adverse effects atdoses 10 times more than were needed for antitumour activity.

PX-316 is a D-3-deoxy-phosphatidyl-myo-inositol that binds to the PHdomain of PKB, trapping it in the cytoplasm and thus preventing PKBactivation. Anti-tumour activity was seen in early xenografts and waswell tolerated.

Allosteric, selective inhibitors of PKB based on a2,3-diphenylquinoxaline core or a 5,6-diphenylpyrazin-2(1H-one core havebeen developed (Merck).

KRX-0401: in a Phase I weekly dosing study conducted in Europe, therecommended Phase II dose was 600/mg/week. Subsequent studies conductedin the U.S. have shown that much higher doses are well tolerated whenthe doses are divided and administered at 4 to 6 hour intervals. Inaddition, it has been shown that KRX-0401 has a very long half-life inthe range of 100 hours. This makes the possibility of a relativenon-toxic, intermittent dosing schedule very plausible.

A phase I trial of API-2 was conducted using a 5-day continuous infusionschedule. Dose levels ranged from 10 mg/sq m/day×5 days to 40 mg/sqm/day×5 days. Initially, courses were repeated every 3 to 4 weeks. Ascumulative toxicity became manifested, the interval between courses waschanged to every 6 weeks. Recommended schedule for Phase II studies is20 mg/sq m/day for 5 days every 6 weeks. A Phase II trial of TCN-P wasconducted in metastatic or recurrent squamous cell carcinoma of thecervix using a 5-day continuous infusion schedule. The starting dose was35 mg/m²×5 days and courses were repeated every 6 weeks.

Further PKB inhibitors include Perifosine from Keryx Biopharmaceuticals.Perifosine is an oral Akt inhibitor which exerts a marked cytotoxiceffect on human tumour cell lines, and is currently being tested inseveral phase II trials for treatment of major human cancers. KRX-0401(Perifosine/NSC 639966) has the structure:

It can be prepared according to Aste Medica patent publication DE4222910or Xenoport patent publication US2003171303.

API-2/TCN (Triciribine) has the structure:

It can be prepared according to Bodor patent publication WO9200988 orRibapharm patent publication WO2003061385.

Enzastaurin hydrochloride has the structure:

It can be prepared according to Eli Lilly patent publicationWO2004006928.

SR 13668 has the structure:

It can be prepared according to SRI International patent publicationUS2004043965.

NL-71-101 has the structure:

It can be prepared according to Biochemistry (2002), 41(32), 10304-10314or Peptor patent publication WO2001091754.

DeveloGen (formerly Peptor) is inyestigating NL-71-101, a protein kinaseB (PKB) inhibitor, for the potential treatment of cancer [466579],[539004]. At the beginning of 2003, the compound was undergoing leadoptimization [495463]. By February 2004, the company was seeking tooutlicense certain development rights to its protein kinase B program[523638].

In 2002, data were published showing that NL-71-101 inhibited theactivity of PKB over PKA, PKG and PKC with IC50 values of 3.7, 9, 36 and104 microM, respectively. NL-71-101 induced apoptosis in OVCAR-3 tumourcells, in which PKB is amplified at concentrations of 50 and 100 microM[466579]. This compound has the structure:

Specific Embodiments:

Embodiments contemplated include combinations in which the anti-canceragent is a PKB inhibitor selected from one or more of the specificcompounds described above.

14. CDK Inhibitors

Definition:

The term “CDK inhibitor” as used herein refers to compounds that inhibitor modulate the activity of cyclin dependent kinases (CDK), includingthe ionic, salt, solvate, isomers, tautomers, N-oxides, ester, prodrugs,isotopes and protected forms thereof (preferably the salts or tautomersor isomers or N-oxides or solvates thereof, and more preferably, thesalts or tautomers or N-oxides or solvates thereof), as described above.

Technical Background:

CDKs play a role in the regulation of the cell cycle, apoptosis,transcription, differentiation and CNS function. Therefore, CDKinhibitors may find application in the treatment of diseases in whichthere is a disorder of proliferation, apoptosis or differentiation suchas cancer. In particular RB+ve tumours may be particularly sensitive toCDK inhibitors. RB-ye tumours may also be sensitive to CDK inhibitors.

Examples of CDK inhibitors which may be used in combinations accordingto the invention include selicidib, alvocidib, 7-hydroxy-staurosporine,JNJ-7706621, BMS-387032, PHA533533, PD332991, ZK-304709 and AZD-5438.

Selicidib, which is the R isomer of roscovitine, and otherwise known asCYC 202, has the chemical name(2R)-2-[[9-(1-methylethyl)-6-[(phenylmethyl)-amino]-9H-purin-2-yl]amino]-1-butanol.It is being evaluated in clinical trials for the potential treatment ofvarious cancers including lymphoid leukaemia, non-small-cell lungcancer, glomerulonephritis, mantle cell lymphoma, multiple myeloma, andbreast cancer. Observed toxicities in clinical trials includenausea/vomiting and asthenia, skin rash and hypokalemia. Othertoxicities included reversible renal impairment and transaminitis, andemesis.

Alvocidib, which is otherwise known as flavopiridol, HMR 1275 or L86-8275, and which has the chemical name5,7-dihydroxy-8-(4-N-methyl-2-hydroxypyridyl)-6′-chloroflavone, is beinginvestigated in clinical trials for the potential treatment of variouscancers including cancer of the esophagus, stomach, prostate, lung andcolon, and also chronic lymphocytic leukaemia, and multiple myeloma,lymphoma; the most common toxicities observed were diarrhea, tumourpain, anemia, dyspnea and fatigue.

7-Hydroxystaurosporine, which is otherwise known as UCN-01 is beingevaluated in clinical trials for the potential treatment of variouscancers including chronic lymphocytic leukaemia, pancreas tumours andrenal tumours; adverse events observed included nausea, headache andhyperglycemia.

JNJ-7706621, which has the chemical nameN3-[4-(aminosulfonyl)-phenyl]-1-(2,6-difluorobenzoyl)-1H-1,2,4-triazole-3,5-diamine,is the subject of pre-clinical testing for the potential treatment ofmelanoma and prostate cancer. BMS-387032 which has the chemical nameN-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]-methyl]thio]-2-thiazolyl]-4-piperidinecarboxamide,has been evaluated in phase I studies as a potential anticancer drug forpatients with metastatic solid tumours such as renal cell carcinomas,non-small-cell lung cancer, head and neck cancers and leiomyosarcoma Thedrug was well tolerated with transient neutropenia noted as the primarytoxicity. Other side-effects included transient liver aminaseelevations, gastrointestinal toxicity, nausea, vomiting, diarrhea andanorexia. PHA533533, which has the chemical name(αS)-N-(5-cyclopropyl-1H-pyrazol-3-yl)-α-methyl-4-(2-oxo-1-pyrrolidinyl)-benzene-acetamide,is the subject of pre-clinical testing for the potential treatment ofvarious cancers such as tumours of the prostate, colon and ovary.PD332991, which has the chemical name8-cyclohexyl-2-[[4-(4-methyl-1-piperazinyl)phenyl]amino]-pyrido[2,3-d]pyrimidin-7(8H)-one,is the subject of pre-clinical testing for the potential treatment ofvarious cancers. Pre-clinical data suggests that it is a highlyselective and potent CDK4 inhibitor, demonstrating marked tumourregression in vivo models.

ZK-304709 is an oral dual specificity CDK and VEGFR kinase inhibitor,described in PCT patent specification No. WO 02/096888, and is thesubject of pre-clinical testing for the potential treatment of variouscancers. AZD-5438 is a selective cyclin-dependent kinase (CDK)Inhibitor, which is in pre-clinical development for the treatment ofsolid cancers. Seliciclib may be prepared for example as described inPCT patent specification No. WO 97/20842, or by processes analogousthereto. Alvocidib, may be prepared for example as described in U.S.Pat. No. 4,900,727 or by processes analogous thereto.7-Hydroxystaurosporine may be prepared for example as described in U.S.Pat. No. 4,935,415, or by processes analogous thereto. JNJ-7706621 maybe prepared for example as described in PCT patent specification No. WO02/057240, or by processes analogous thereto. BMS-387032 may be preparedfor example as described in PCT patent specification No. WO 01/44242, orby processes analogous thereto. PHA533533 may be prepared for example asdescribed in U.S. Pat. No. 6,455,559, or by processes analogous thereto.PD332991, may be prepared for example as described in PCT patentspecification No. WO 98/33798, or by processes analogous thereto.ZK-304709 may be prepared for example as described in PCT patentspecification No. WO 02/096888, or by processes analogous thereto.

Preferences and Specific Embodiments:

Embodiments contemplated include combinations in which the anti-canceragent is a CDK inhibitor selected from one or more of the specificcompounds described above. Thus, preferred CDK inhibitors for use incombinations according to the invention include seliciclib, alvocidib,7-hydroxystaurosporine, JNJ-7706621, BMS-387032, PHA533533, PD332991,ZK-304709 and AZD-5438.

Posology:

The CDK inhibitor may be administered for example in a daily dosage offor example 0.5 to 2500 mg, more preferably 10 to 1000 mg, oralternatively 0.001 to 300 mg/kg, more preferably 0.01 to 100 mg/kg,particularly for seliciclib, in a dosage of 10 to 50 mg; for alvocidib,in a dosage in accordance with the above-mentioned U.S. Pat. No.4,900,727; for 7-hydroxystaurosporine in a dosage of 0.01 to 20 mg/kg;for JNJ-7706621 in a dosage of 0.001 to 300 mg/kg; for BMS-387032 in adosage of 0.001 to 100 mg/kg more preferably 0.01 to 50 mg/kg, and mostpreferably 0.01 to 20 mg/kg; for PHA533533 in a dosage of 10 to 2500 mg;for PD332991 in a dosage of 1 to 100 mg/kg; and for ZK-304709 in adosage of 0.5 to 1000 mg preferably 50 to 200 mg.

These dosages may be administered for example once, twice or more percourse of treatment, which may be repeated for example every 7, 14, 21or 28 days.

15. COX-2 Inhibitors

Definition:

The term “COX-2 inhibitor” is used herein to define compounds whichinhibit or modulate the activity of the cyclo-oxygenase-2 (COX-2)enzyme, including the ionic, salt, solvate, isomers, tautomers,N-oxides, ester, prodrugs, isotopes and protected forms thereof(preferably the salts or tautomers or isomers or N-oxides or solvatesthereof, and more preferably, the salts or tautomers or N-oxides orsolvates thereof), as described above.

Biological Activity:

The COX-2 inhibitors working via one or more pharmacological actions asdescribed herein have been identified as suitable anti-cancer agents.

Technical Background:

Recently, research in cancer chemotherapy has focused on the role of thecyclo-oxygenase-2 (COX-2) enzyme. Epidemiological studies have shownthat people who regularly take non-steroidal anti-inflammatory drugs(NSAIDs), for example aspirin and ibuprofen to treat conditions such asarthritis, have lower rates of colorectal polyps, colorectal cancer, anddeath due to colorectal cancer. NSAIDs block cyclooxygenase enzymes,which are produced by the body in inflammatory processes, and which arealso produced by pre-cancerous tissues. For example in colon cancers, adramatic increase of COX-2 levels is observed. One of the key factorsfor tumour growth is the supply of blood to support its increased size.Many tumours can harness chemical pathways that prompt the body tocreate a web of new blood vessels around the cancer, a process calledangiogenesis. COX-2 is believed to have a role in this process. It hastherefore been concluded that inhibition of COX-2 may be effective fortreating cancer, and COX-2 inhibitors have been developed for thispurpose. For example celecoxib, which has the chemical name4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide,is a selective COX-2 inhibitor that is being investigated for thetreatment of various cancers including bladder and esophageal cancer,renal cell carcinoma, cervical cancer, breast cancer, pancreatic cancernon-Hodgkin's lymphoma and non-small cell lung cancer.

Posology:

The COX-2 inhibitor (for example celecoxib) can be administered in adosage such as 100 to 200 mg.

These dosages may be administered for example once, twice or more percourse of treatment, which may be repeated for example every 7, 14, 21or 28 days.

Problems:

The most common adverse effects are headache, abdominal pain, dyspepsia,diarrhea, nausea, flatulence and insomnia. There is a need to provide ameans for the use of lower dosages of COX-2 inhibitors to reduce thepotential for adverse toxic side effects to the patient.

Preferences and Specific Embodiments:

In one embodiment the COX-2 inhibitor is celecoxib. Celecoxib iscommercially available for example from Pfizer Inc under the trade nameCelebrex, or may be prepared for example as described in PCT patentspecification No. WO 95/15316, or by processes analogous thereto.

16. HDAC Inhibitors

Definition:

The term “HDAC inhibitor” is used herein to define compounds whichinhibit or modulate the activity of histone deacetylases (HDAC),including the ionic, salt, solvate, isomers, tautomers, N-oxides, ester,prodrugs, isotopes and protected forms thereof (preferably the salts ortautomers or isomers or N-oxides or solvates thereof, and morepreferably, the salts or tautomers or N-oxides or solvates thereof), asdescribed above.

Biological Activity:

The HDAC inhibitors working via one or more pharmacological actions asdescribed herein have been identified as suitable anti-cancer agents.

Technical Background:

Reversible acetylation of histones is a major regulator of geneexpression that acts by altering accessibility of transcription factorsto DNA. In normal cells, histone deacetylase (HDA or HDAC) and histoneacetyltrasferase (HDA) together control the level of acetylation ofhistones to maintain a balance. Inhibition of HDA results in theaccumulation of hyperacetylated histones, which results in a variety ofcellular responses. Inhibitors of HDA (HDAI) have been studied for theirtherapeutic effects on cancer cells. Recent developments in the field ofHDAI research have provided active compounds, both highly efficaciousand stable, that are suitable for treating tumours.

Accruing evidence suggests that HDAI are even more efficacious when usedin combination with other chemotherapeutic agents. There are bothsynergistic and additive advantages, both for efficacy and safety.Therapeutic effects of combinations of chemotherapeutic agents with HDAIcan result in lower safe dosage ranges of each component in thecombination.

The study of inhibitors of histone deacetylases (HDAC) indicates thatindeed these enzymes play an important role in cell proliferation anddifferentiation. The inhibitor Trichostatin A (TSA) causes cell cyclearrest at both G1 and G2 phases, reverts the transformed phenotype ofdifferent cell lines, and induces differentiation of Friend leukaemiacells and others. TSA (and suberoylanilide hydroxamic acid SAHA) havebeen reported to inhibit cell growth, induce terminal differentiation,and prevent the formation of tumours in mice (Finnin et al., Nature,401:188-193, 1999).

Trichostatin A has also been reported to be useful in the treatment offibrosis, e.g. liver fibrosis and liver chirrhosis. (Geerts et al.,European Patent Application EP0 827 742, published 11 Mar. 1998).

Preferences and Specific Embodiments:

Preferred HDAC inhibitors for use in accordance with the invention areselected from TSA, SAHA, JNJ-16241199, LAQ-824, MGCD-0103 and PXD-101(referred to above).

Thus, synthetic inhibitors of histone deacetylases (HDAC) which aresuitable for use in the present invention include JNJ-16241199 fromJohnson and Johnson Inc, LAQ-824 from Novartis, MGCD-0103 fromMethylGene, and PXD-101 from Prolifix.

JNJ-16241199 has the following structure:

MGCD-0103 has the structure:

LAQ-824 has the structure:

Other inhibitors of histone deacetylases (HDAC) which are suitable foruse in the present invention include, but are not limited to, thepeptide chlamydocin, and A-173, also from Abbott Laboratories.

A-173 is a succinimide macrocyclic compound with the followingstructure:

Posology:

In general, for HDAC inhibitors it is contemplated that atherapeutically effective amount would be from 0.005 mg/kg to 100 mg/kgbody weight, and in particular from 0.005 mg/kg to 10 mg/kg body weight.It may be appropriate to administer the required dose as two, three,four or more sub-doses at appropriate intervals throughout the day. Saidsub-doses may be formulated as unit dosage forms, for example,containing 0.5 to 500 mg, and in particular 10 mg to 500 mg of activeingredient per unit dosage form.

17. DNA Methylase Inhibitors

Definition:

The term “DNA methylase inhibitor” or “DNA methyltransferase inhibitor”as used herein refers to a compound which directly or indirectlyperturbs, disrupts, blocks, modulates or inhibits the methylation ofDNA, including the ionic, salt, solvate, isomers, tautomers, N-oxides,ester, prodrugs, isotopes and protected forms thereof (preferably thesalts or tautomers or isomers or N-oxides or solvates thereof, and morepreferably, the salts or tautomers or N-oxides or solvates thereof), asdescribed above.

Biological Activity:

The DNA methylase inhibitors working via one or more pharmacologicalactions as described herein have been identified as suitable anti-canceragents.

Technical Background:

One target for cancer chemotherapy is DNA synthesis, which may depend onappropriate methylation of tumour DNA. Compounds which directly orindirectly perturb, disrupt, block, modulate or inhibit the methylationof DNA may therefore be useful anticancer drugs.

The DNA methylase inhibitor temozolomide is used for the treatment ofglioblastoma multiforme, and is also being investigated and used for thetreatment of malignant glioma at first relapse and first-line treatmentof patients with advanced metastatic malignant melanoma. This compoundundergoes rapid chemical conyersion at physiological pH to the activecompound, monomethyl triazeno imidazole carboxamide (MTIC) which isresponsible for the methylation of DNA at the O⁶ position of guanineresidues (which appears to lead to a suppression in expression of DNAmethyltransferase and so produce hypomethylation).

Problems:

The most common side effects associated with temozolomide therapy arenausea, vomiting, headache, fatigue, and constipation. There is a needto increase the inhibitory efficacy of DNA\methylase inhibitors and toprovide a means for the use of lower dosages of signaling Inhibitors toreduce the potential for adverse toxic side effects to the patient.

Preferences and Specific Embodiments:

In one embodiment, the DNA methylase inhibitor is temozolomide(3,4-dihydro-3-methyl-4-oxoimidazo[5,1-d]-as-tetrazine-8-carboxamide).Temozolomide is commercially available for example from ScheringCorporation under the trade name Temodar, or may be prepared for exampleas described in German patent specification No. 3231255, or by processesanalogous thereto.

Posology:

The DNA methylating agent (for example temozolomide) can be administeredin a dosage such as 0.5 to 2.5 mg per square meter (mg/m²) of bodysurface area, particularly about 1.3 mg/m². These dosages may beadministered for example once, twice or more per course of treatment,which may be repeated for example every 7, 14, 21 or 28 days.

18. Proteasome Inhibitors

Definition:

The term “proteasome inhibitor” as used herein refers to compounds whichdirectly or indirectly perturb, disrupt, block, modulate or inhibit thehalf-life of many short-lived biological processes, such as thoseinvolved in the cell cycle. The term therefore embraces compounds whichblock the action of proteasomes (large protein complexes that areinvolved in the turnover of other cellular proteins). The term alsoembraces the ionic, salt, solvate, isomers, tautomers, N-oxides, ester,prodrugs, isotopes and protected forms thereof (preferably the salts ortautomers or isomers or N-oxides or solvates thereof, and morepreferably, the salts or tautomers or N-oxides or solvates thereof), asdescribed above.

Biological Activity:

The proteasome inhibitors working via one or more pharmacologicalactions as described herein have been identified as suitable anti-canceragents.

Technical Background:

Another class of anticancer agents are the proteasome inhibitors.Proteasomes control the half-life of many short-lived biologicalprocesses, such as those involved in the cell cycle. Therefore,proteasome malfunction can lead to abnormal regulation of the cell cycleand uncontrolled cell growth.

The cell cycle is controlled by both positive and negative signals. In anormal cell, proteasomes break down proteins that inhibit the cellcycle, such as cyclin-dependent kinase inhibitors. Inhibition ofproteasome function causes cell cycle arrest and cell death. Tumourcells are more susceptible to these effects than normal cells, in partbecause they divide more rapidly and in part because many of theirnormal regulatory pathways are disrupted. The mechanism for thedifferential response of normal and cancer cells to proteasomeinhibition is not fully understood. Overall, cancer cells are moresusceptible to proteasome inhibitors and, as a result, these inhibitorsmay be an effective treatment for certain cancers.

One such proteasome inhibitor is bortezimib, which has the chemical name[(1R)-3-methyl-1-[[(2S)-1-oxo-3-phenyl-2-[(pyrazinylcarbonyl)amino]propyl]amino]butyl]-boronicacid. Bortezimib specifically interacts with a key amino acid, namelythreonine, within the catalytic site of the proteasome. Bortezimib isbeing used for the treatment of multiple myeloma and also for a numberof other cancers, including leukemia and lymphoma, and prostate,pancreatic and colorectal carcinoma.

Problems:

The most common side effects with bortezimib are nausea, tiredness,diarrhea, constipation, decreased platelet blood count, fever, vomiting,and decreased appetite. Bortezimib can also cause peripheral neuropathy.

Thus, there is a need to provide a means for the use of lower dosages toreduce the potential of adverse toxic side effects to the patient.

Preferences and Specific Embodiments:

Preferred proteasome inhibitors for use in accordance with the inventioninclude bortezimib. Bortezimib is commercially available for examplefrom Millennium Pharmaceuticals Inc under the trade name Velcade, or maybe prepared for example as described in PCT patent specification No. WO96/13266, or by processes analogous thereto.

Posology:

The proteasome inhibitor (such as bortezimib) can be administered in adosage such as 100 to 200 mg/m². These dosages may be administered forexample once, twice or more per course of treatment, which may berepeated for example every 7, 14, 21 or 28 days.

The antibiotic bleomycin may also be used as a cytotoxic agent as ananti-cancer agent according to the invention.

Anti-Cancer Agent Combinations

The combinations of the Invention may comprise two or more ancillarycompounds. In such embodiments, the ancillary compounds may beanti-cancer agents. In such embodiments, the two or more anticanceragents may be independently selected from carboplatin, cisplatin, taxol,taxotere, gemcitablne, and vinorelbine. Preferably the two or morefurther anti-cancer agents are carboplatin, taxol and vinorelbine, orcarboplatin and taxol.

Combinations of compounds of Formula (I) with carboplatin, taxol andvinorelbine or combinations of compounds of Formula (I) with carboplatinand taxol, are particularly suitable for treating Non-Small cell lungcancer.

In one embodiment, the two or more anti-cancer agents are independentlyselected from 5-FU, leucovorin, oxaliplatin, CPT 11, and bevacizumab.Preferably, the two or more anti-cancer agents are 5-FU, leucovorin andCPT 11 or 5-FU, leucovorin and oxaliplatin.

Combinations of compounds of Formula (I) with 5-FU, leucovorin and CPT11 or a combination of compounds of Formula (I) with 5-FU, leucovorinand oxaliplatin, are particularly suitable for treating colon cancer.

In one embodiment, the two or more anti-cancer agents are independentlyselected from methotrexate, taxanes, anthracyclines e.g. doxorubicin,herceptin, 5-FU, and cyclophosphamide. In one embodiment, the two ormore anti-cancer agents are independently selected from taxanes,anthracyclines e.g. doxorubicin, herceptin, 5-FU, and cyclophosphamide.In one embodiment, the two or more anti-cancer agents are independentlyselected from 5-FU, methotrexate, cyclophosphamide and doxorubicin.Preferably the two or more anti-cancer agents are 5-FU, methotrexate andcyclophosphamide or 5-FU, doxorubicin and cyclophosphamide ordoxorubicin and cyclophosphamide.

Combinations of compounds of Formula (I) with 5-FU, methotrexate andcyclophosphamide, or a combination of compounds of Formula (I) with5-FU, doxorubicin and cyclophosphamide, or combinations of compounds ofFormula (I) with doxorubicin and cyclophosphamide, are particularlysuitable for treating breast cancer.

In one embodiment, the two or more anti-cancer agents are independentlyselected from cyclophosphamide, doxorubicin (hydroxydaunorubicin),vincristine, and prednisone. Preferably the two or more anti-canceragents are cyclophosphamide, doxorubicin (hydroxydaunorubicin),vincristine and prednisone, or cyclophosphamide, vincristine andprednisone.

Combinations of compounds of Formula (I) with cyclophosphamide,doxorubicin (hydroxydaunorubicin), vincristine and prednisone areparticularly suitable for treating non Hodgkin's lymphoma (and inparticular high grade non Hodgkin's lymphoma). Combinations of compoundsof Formula (I) with cyclophosphamide, vincristine and prednisone areparticularly suitable for treating non Hodgkin's lymphoma (and inparticular low grade non Hodgkin's lymphoma).

In one embodiment, the two or more anti-cancer agents are independentlyselected from vincristine, doxorubicin, and dexamethasone. Preferablythe two or more anti-cancer agents are vincristine, doxorubicin anddexamethasone.

Combinations of compounds of Formula (I) with vincristine, doxorubicinand dexamethasone are particularly suitable for treating multiplemyeloma.

In one embodiment, the two or more anti-cancer agents are independentlyselected from fludarabine and rituxamab. Preferably the two or moreanti-cancer agents are fludarabine and rituxamab.

Combinations of compounds of Formula (I) with fludarabine and rituxamabare particularly suitable for treating chronic lymphocytic leukemia.

In one embodiment the combination of the invention optionally excludescombination of two or more of the following anti-cancer agents selectedfrom a topoisomerase inhibitor, an alkylating agent, a antimetabolite,DNA binders, monoclonal antibodies, signal transduction inhibitors andmicrotubule inhibitors (tubulin targeting agents), such as cisplatin,cyclophosphamide, doxorubicin, irinotecan, fludarabine, 5FU, taxanes andmitomycin C.

In one embodiment the combination of the invention includes at least oneanti-cancer agent selected from an antiandrogen, a histone deacetylaseinhibitor (HDAC), cylcooxygenase-2 (COX-2) inhibitor, proteasomeinhibitor, DNA methylation inhibitor and a CDK inhibitor.

Specific Combinations of the Invention

Particular combinations according to the invention Include compounds ofFormula (I) and subgroups thereof as defined herein with the followingtwo or more anti-cancer agents:

For cancer (and in particular acute myeloid leukemia) treatment, two ormore anti-cancer agents independently selected from two or more ofanthracycline, Ara C (a.k.a. Cytarabine), 6-mercaptopurine,methotrexate, mitoxantrone, daunorubicin, idarubicin, gemtuzumabozogamicin and granulocyte colony stimulating factors. Alternatively,the two or more anti-cancer agents may be independently selected fromtwo or more of anthracycline, Ara C (a.k.a. Cytarabine), daunorubicin,idarubicin, gemtuzumab ozogamicin and granulocyte colony stimulatingfactors.

For cancer (and in particular breast cancer) treatment, two or moreanti-cancer agents independently selected from bevacizumab, taxanes,methotrexate, paclitaxel, docetaxel, gemcitabine, anastrozole,exemestane, letrozole, tamoxifen, doxorubicin, herceptin,5-fluorouracil, cyclophosphamide, epirubicin and capecitabine,particularly 5-FU, methotrexate and cyclophosphamide; 5FU, doxorubicinand cyclophosphamide; or doxorubicin and cyclophosphamide. Preferably,for cancer (and in particular breast cancer) treatment, the two or moreanti-cancer agents may also be independently selected from taxanes,methotrexate, paclitaxel, docetaxel, gemcitabine, anastrozole,exemestane, letrozole, tamoxifen, doxorubicin, herceptin,5-fluorouracil, cyclophosphamide, epirubicin and capecitabine,particularly 5-FU, methotrexate and cyclophosphamide; 5FU, doxorubicinand cyclophosphamide; or doxorubicin and cyclophosphamide.

Typical dosing regimens include:

-   -   Cyclophosphamide at 100 mg/m² PO Daily×14 days, Doxorubicin at        30 mg/m² IV Day 1 & day 8 and fluorouracil at 500 mg/m² IV Day 1        & day 8, repeated every 28 days for up to 6 cycles    -   Cyclophosphamide at 600 mg/m² IV Day 1 and Doxorubicin at 60        mg/m² IV Day 1, repeated every 21 days for up to 4 cycles

For cancer (and in particular chronic lymphocytic leukemia (CLL))treatment, two or more anti-cancer agents independently selected fromalemtuzumab, chlorambucil, cyclophosphamide, vincristine, predinisolone,fludarabine, mitoxantrone and rituximab/rituxamab, particularlyfludarabine and rituxamab. Preferably, for cancer (and in particularchronic lymphocytic leukemia (CLL)) treatment, the two or moreanti-cancer agents are independently selected from chlorambucil,cyclophosphamide, vincristine, predinisolone, fludarabine, mitoxantroneand rituximab/rituxamab, particularly fludarabine and rituxamab.

For cancer (and in particular chronic myeloid leukemia (CML)) treatment,two or more anti-cancer agents independently selected from hydroxyurea,cytarabine, and imatinib.

For cancer (and in particular Colon Cancer treatment), two or moreanti-cancer agents independently selected from cetuximab,5-Fluorouracil, leucovorin, irinotecan, oxaliplatin, raltirexed,capecitabine, bevacizumab, oxaliplatin, CPT 11, particularly5-Fluorouracil, Leucovorin and CPT 11 or Fluorouracil, Leucovorin andOxaliplatin.

Alternatively, for cancer (and in particular Colon Cancer treatment),two or more anti-cancer agents independently selected from5-Fluorouracil, leucovorin, irinotecan, oxaliplatin, raltirexed,capecitabine, bevacizumab, oxaliplatin, CPT 11 and Avastin, particularly5-Fluorouracil, Leucovorin and CPT 11 or Fluorouracil, Leucovorin andOxaliplatin.

Typical dosing regimens include:

-   -   Fluorouracil at 400-425 mg/m² IV Days 1 to 5 and Leucovorin at        20 mg/m² IV Days 1 to 5, repeated every 28 days for 6 cycles    -   Irinotecan at 100-125 mg/m² IV over 90 minutes Days 1, 8, 15 &        22, Folinic acid at 20 mg/m2 IV Days 1, 8, 15 & 22, and        Fluorouracil at 400-500 mg/m2 IV Days 1, 8, 15 & 22, repeated        every 42 days until disease progression    -   Oxaliplatin at 85 mg/m2 IV in 500 mL of D5W over 120 minutes Day        1, Folinic acid at 200 mg/m2 IV over 120 minutes Days 1 & 2,        Fluorouracil at 400 mg/m2 IV bolus, after Folinic Acid, Days 1 &        2, then Fluorouracil at 600 mg/m2 CIV over 22 hours Days 1 & 2,        repeated every 12 days for up to 12 cycles

For cancer (and in particular multiple myeloma treatment), two or moreanti-cancer agents independently selected from vincristine, doxorubicin,dexamethasone, melphalan, prednisone, cyclophosphaimde, etoposide,pamidronate, zoledronate and bortezomib, particulary vincristine,doxorubicin and dexamethasone.

For cancer (and in particular Non-Hodgkin's lymphoma treatment), two ormore anti-cancer agents independently selected from cyclophosphamide,doxorubicin/hydroxydaunorubicin, vincristine/Onco-TCS (V/O),prednisolone, methotrexate, cytarabine, bleomycin, etoposide,rituximab/rituxamab, fludarabine, cisplatin, and ifosphamide,particularly cyclophosphamide, doxorubicin (hydroxydaunorubicin),vincristine and prednisone for high grade NHL or cyclophosphamide,vincristine and prednisone for low grade NHL.

For cancer (and in particular Non Small Cell Lung Cancer (NSCLC))treatment, two or more anti-cancer agents may be independently selectedfrom bevacizumab, gefitinib, erlotinib, cisplatin, carboplatin,etoposide, mitomycin, vinblastine, paclitaxel, docetaxel, gemcitabineand vinorelbine, especially taxol, vinorelbine and carboplatin or taxoland carboplatin. Particulalrly preferred for cancer (and in particularNon Small Cell Lung Cancer (NSCLC)) treatment, two or more anti-canceragents are Independently selected from cisplatin, carboplatin,etoposide, mitomycin, vinblastine, paclitaxel, docetaxel, gemcitabineand vinorelbine, especially taxol, vinorelbine and carboplatin or taxoland carboplatin.

Typical dosing regimens include:

-   -   Gemcitabine at 1000 mg/m² IV Days 1, 8 & 15, and Cisplatin at        75-100 mg/m² IV Day 1, repeated every 28 days for 4-6 cycles    -   Paclitaxel at 135-225 mg/m² IV over 3 hrs Day 1 and Carboplatin        at AUC 6.0 IV Day 1, repeated every 21 days for 4-6 cycles    -   Docetaxel at 75 mg/m² IV Day 1, and Carboplatin at AUC 5 or 6 IV        Day 1, repeated every 21 days for 4-6 cycles    -   Docetaxel at 75 mg/m² IV Day 1, and Cisplatin at 75 mg/m² IV Day        1, repeated every 21 days for 4-6 cycles

For cancer (and in particular ovarian cancer) treatment, two or moreanti-cancer agents independently selected from platinum compounds (forexample Cisplatin, Carboplatin), taxol, doxorubicin, liposomaldoxorubicin, paclitaxel, docetaxel, gemcitabine, melphalan andmitoxantrone.

For cancer (and in in particular prostate cancer) treatment, two or moreanti-cancer agents independently selected from mitoxantrone, prednisone,buserelin, goserelin, bicalutamide, nilutamide, flutamide, cyproteroneacetate, megestrol/megestrel, diethylstilboestrol, docetaxel,paclitaxel, zoledronic acid and taxotere.

Pharmaceutical Formulations

While it is possible for the active compounds in the combinations of theinvention to be administered alone, it is preferable to present them asa pharmaceutical composition (e.g. formulation) comprising at least oneactive compound of the invention together with one or morepharmaceutically acceptable carriers, adjuvants, excipients, diluents,fillers, buffers, stabilisers, preservatives, lubricants, or othermaterials well known to those skilled in the art and optionally othertherapeutic or prophylactic agents

Thus, the present invention further provides pharmaceuticalcompositions, as defined above, and methods of making a pharmaceuticalcomposition comprising admixing at least one active compound, as definedabove, together with one or more pharmaceutically acceptable carriers,excipients, buffers, adjuvants, stabilizers, or other materials, asdescribed herein.

The term “pharmaceutically acceptable” as used herein pertains tocompounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of a subject (e.g. human) without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio. Each carrier,excipient, etc. must also be “acceptable” in the sense of beingcompatible with the other ingredients of the formulation.

Pharmaceutical compositions containing compounds of the formula (I) canbe formulated in accordance with known techniques, see for example,Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton,Pa., USA.

Accordingly, in a further aspect, the invention provides compounds ofthe formula (I) and sub-groups thereof as defined herein in the form ofpharmaceutical compositions.

The pharmaceutical compositions can be in any form suitable for oral,parenteral, topical, intranasal, ophthalmic, otic, rectal,intra-yaginal, or transdermal administration. Where the compositions areintended for parenteral administration, they can be formulated forintravenous, intramuscular, intraperitoneal, subcutaneous administrationor for direct delivery into a target organ or tissue by injection,Infusion or other means of delivery. The delivery can be by bolusInjection, short term infusion or longer term infusion and can be viapassive delivery or through the utilisation of a suitable infusion pump.

Pharmaceutical formulations adapted for parenteral administrationinclude aqueous and non-aqueous sterile injection solutions which maycontain anti-oxidants, buffers, bacterlostats, co-solvents, organicsolvent mixtures, cyclodextrin complexation agents, emulsifying agents(for forming and stabilizing emulsion formulations), liposome componentsfor forming liposomes, gellable polymers for forming polymeric gels,lyophilisation protectants and combinations of agents for, inter alla,stabilising the active ingredient in a soluble form and rendering theformulation isotonic with the blood of the intended recipient.Pharmaceutical formulations for parenteral administration may also takethe form of aqueous and non-aqueous sterile suspensions which mayinclude suspending agents and thickening agents (R. G. Strickly,Solubilizing Excipients in oral and injectable formulations,Pharmaceutical Research, Vol 21(2) 2004, p 201-230).

Liposomes are closed spherical vesicles composed of outer lipid bilayermembranes and an inner aqueous core and with an overall diameter of <100μm. Depending on the level of hydrophobicity, moderately hydrophobicdrugs can be solubilized by liposomes if the drug becomes encapsulatedor intercalated within the liposome. Hydrophobic drugs can also besolubilized by liposomes if the drug molecule becomes an integral partof the lipid bilayer membrane, and in this case, the hydrophobic drug isdissolved in the lipid portion of the lipid bilayer.

The formulations may be presented in unit-dose or multi-dose containers,for example sealed ampoules and vials, and may be stored in afreeze-dried (lyophilised) condition requiring only the addition of thesterile liquid carrier, for example water for injections, immediatelyprior to use.

The pharmaceutical formulation can be prepared by lyophilising acompound of formula (I) as defined herein, or sub-groups thereof.Lyophilisation refers to the procedure of freeze-drying a composition.Freeze-drying and lyophilisation are therefore used herein as synonyms.

Extemporaneous injection solutions and suspensions may be prepared fromsterile powders, granules and tablets.

Pharmaceutical compositions of the present invention for parenteralinjection can also comprise pharmaceutically acceptable sterile aqueousor non-aqueous solutions, dispersions, suspensions or emulsions as wellas sterile powders for reconstitution into sterile injectable solutionsor dispersions just prior to use. Examples of suitable aqueous andnonaqueous carriers, diluents, solvents or vehicles include water,ethanol, polyols (such as glycerol, propylene glycol, polyethyleneglycol, and the like), carboxymethylcellulose and suitable mixturesthereof, vegetable oils (such as olive oil), and injectable organicesters such as ethyl oleate. Proper fluidity can be maintained, forexample, by the use of coating materials such as lecithin, by themaintenance of the required particle size in the case of dispersions,and by the use of surfactants.

The compositions of the present invention may also contain adjuvantssuch as preservatives, wetting agents, emulsifying agents, anddispersing agents. Prevention of the action of microorganisms may beensured by the inclusion of various antibacterial and antifungal agents,for example, paraben, chlorobutanol, phenol sorbic acid, and the like.It may also be desirable to include isotonic agents such as sugars,sodium chloride, and the like. Prolonged absorption of the injectablepharmaceutical form may be brought about by the inclusion of agentswhich delay absorption such as aluminum monostearate and gelatin.

In one preferred embodiment of the invention, the pharmaceuticalcomposition is in a form suitable for i.v. administration, for exampleby injection or infusion. For intravenous administration, the solutioncan be dosed as is, or can be injected into an infusion bag (containinga pharmaceutically acceptable excipient, such as 0.9% saline or 5%dextrose), before administration.

In another preferred embodiment, the pharmaceutical composition is in aform suitable for sub-cutaneous (s.c.) administration.

Pharmaceutical dosage forms suitable for oral administration includetablets, capsules, caplets, pills, lozenges, syrups, solutions, powders,granules, elixirs and suspensions, sublingual tablets, wafers or patchesand buccal patches.

Thus, tablet compositions can contain a unit dosage of active compoundtogether with an inert diluent or carrier such as a sugar or sugaralcohol, eg; lactose, sucrose, sorbitol or mannitol; and/or a non-sugarderived diluent such as sodium carbonate, calcium phosphate, calciumcarbonate, or a cellulose or derivative thereof such as methylcellulose, ethyl cellulose, hydroxypropyl methyl cellulose, and starchessuch as corn starch. Tablets may also contain such standard Ingredientsas binding and granulating agents such as polyvinylpyrrolidone,disintegrants (e.g. swellable crosslinked polymers such as crosslinkedcarboxymethylcellulose), lubricating agents (e.g. stearates),preservatives (e.g. parabens), antioxidants (e.g. BHT), buffering agents(for example phosphate or citrate buffers), and effervescent agents suchas citrate/bicarbonate mixtures. Such excipients are well known and donot need to be discussed in detail here.

Capsule formulations may be of the hard gelatin or soft gelatin varietyand can contain the active component in solid, semi-solid, or liquidform. Gelatin capsules can be formed from animal gelatin or synthetic orplant derived equivalents thereof.

The solid dosage forms (eg; tablets, capsules etc.) can be coated orun-coated, but typically have a coating, for example a protective filmcoating (e.g. a wax or varnish) or a release controlling coating. Thecoating (e.g. a Eudragit™ type polymer) can be designed to release theactive component at a desired location within the gastro-intestinaltract. Thus, the coating can be selected so as to degrade under certainpH conditions within the gastrointestinal tract, thereby selectivelyrelease the compound in the stomach or in the ileum or duodenum.

Instead of, or in addition to, a coating, the drug can be presented in asolid matrix comprising a release controlling agent, for example arelease delaying agent which may be adapted to selectively release thecompound under conditions of varying acidity or alkalinity in thegastrointestinal tract. Alternatively, the matrix material or releaseretarding coating can take the form of an erodible polymer (e.g. amaleic anhydride polymer) which is substantially continuously eroded asthe dosage form passes through the gastrointestinal tract. As a furtheralternative, the active compound can be formulated in a delivery systemthat provides osmotic control of the release of the compound. Osmoticrelease and other delayed release or sustained release formulations maybe prepared in accordance with methods well known to those skilled inthe art.

The pharmaceutical compositions comprise from approximately 1% toapproximately 95%, preferably from approximately 20% to approximately90%, active ingredient. Pharmaceutical compositions according to theinvention may be, for example, in unit dose form, such as in the form ofampoules, vials, suppositories, dragées, tablets or capsules.

Pharmaceutical compositions for oral administration can be obtained bycombining the active ingredient with solid carriers, if desiredgranulating a resulting mixture, and processing the mixture, if desiredor necessary, after the addition of appropriate excipients, intotablets, dragee cores or capsules. It is also possible for them to beincorporated into plastics carriers that allow the active ingredients todiffuse or be released in measured amounts.

The compounds of the invention can also be formulated as soliddispersions. Solid dispersions are homogeneous extremely fine dispersephases of two or more solids. Solid solutions (molecularly dispersesystems), one type of solid dispersion, are well known for use inpharmaceutical technology (see (Chiou and Riegelman, J. Pharm. Sci., 60,1281-1300 (1971)) and are useful in increasing dissolution rates andincreasing the bioavailability of poorly water-soluble drugs.

This invention also provides solid dosage forms comprising the solidsolution described above. Solid dosage forms include tablets, capsulesand chewable tablets. Known excipients can be blended with the solidsolution to provide the desired dosage form. For example, a capsule cancontain the solid solution blended with (a) a disintegrant and alubricant, or (b) a disintegrant, a lubricant and a surfactant. A tabletcan contain the solid solution blended with at least one disintegrant, alubricant, a surfactant, and a glidant. The chewable tablet can containthe solid solution blended with a bulking agent, a lubricant, and ifdesired an additional sweetening agent (such as an artificialsweetener), and suitable flavours.

The pharmaceutical formulations may be presented to a patient in“patient packs” containing an entire course of treatment in a singlepackage, usually a blister pack. Patient packs have an advantage overtraditional prescriptions, where a pharmacist divides a patient's supplyof a pharmaceutical from a bulk supply, in that the patient always hasaccess to the package insert contained in the patient pack, normallymissing in patient prescriptions. The inclusion of a package insert hasbeen shown to improve patient compliance with the physician'sinstructions.

Compositions for topical use include ointments, creams, sprays, patches,gels, liquid drops and inserts (for example intraocular inserts). Suchcompositions can be formulated in accordance with known methods.

Examples of formulations for rectal or intra-vaginal administrationinclude pessaries and suppositories which may be, for example, formedfrom a shaped moldable or waxy material containing the active compound.

Compositions for administration by inhalation may take the form ofinhalable powder compositions or liquid or powder sprays, and can beadministrated in standard form using powder inhaler devices or aerosoldispensing devices. Such devices are well known. For administration byinhalation, the powdered formulations typically comprise the activecompound together with an inert solid powdered diluent such as lactose.

The compounds of the formula (I) will generally be presented in unitdosage form and, as such, will typically contain sufficient compound toprovide a desired level of biological activity. For example, aformulation may contain from 1 nanogram to 2 grams of active ingredient,e.g. from 1 nanogram to 2 milligrams of active ingredient. Within thisrange, particular sub-ranges of compound are 0.1 milligrams to 2 gramsof active ingredient (more usually from 10 milligrams to 1 gram, e.g. 50milligrams to 500 milligrams), or 1 microgram to 20 milligrams (forexample 1 microgram to 10 milligrams, e.g. 0.1 milligrams to 2milligrams of active ingredient).

For oral compositions, a unit dosage form may contain from 1 milligramto 2 grams, more typically 10 milligrams to 1 gram, for example 50milligrams to 1 gram, e.g. 100 milligrams to 1 gram, of active compound.

The active compound will be administered to a patient in need thereof(for example a human or animal patient) in an amount sufficient toachieve the desired therapeutic effect.

Protein Kinase Inhibitory Activity

The activity of the inhibitors of protein kinase A and protein kinase Bcan be measured using the assays set forth in the examples below and thelevel of activity exhibited by a given compound can be defined in termsof the IC50 value. Preferred compounds for use in the combinations ofthe present invention are compounds having an IC₅₀ value of less than 1μM, more preferably less than 0.1 μM, against protein kinase B.

Therapeutic Uses

Prevention or Treatment of Proliferative Disorders

The combinations of the invention are expected to be useful in providinga means of preventing the growth of or inducing apoptosis of neoplasias.It is therefore anticipated that the combinations will prove useful intreating or preventing proliferative disorders such as cancers. Inparticular tumours with deletions or inactivating mutations in PTEN orloss of PTEN expression or rearrangements in the (T-cell lytmphocyte)TCL-1 gene may be particularly sensitive to PKB inhibitors. Tumourswhich have other abnormalities leading to an upregulated PKB pathwaysignal may also be particularly sensitive to inhibitors of PKB. Examplesof such abnormalities include but are not limited to overexpression ofone or more PI3K subunits, over-expression of one or more PKB Isoforms,or mutations in PI3K, PDK1, or PKB which lead to an increase in thebasal activity of the enzyme in question, or upregulation oroverexpression or mutational activation of a growth factor receptor suchas a growth factor selected from the epidermal growth factor receptor(EGFR), fibroblast growth factor receptor (FGFR), platelet derivedgrowth factor receptor (PDGFR), insulin-like growth factor 1 receptor(IGF-1R) and vascular endothelial growth factor receptor (VEGFR)families.

It is also envisaged that the combinations of the invention will beuseful in treating other conditions which result from disorders inproliferation or survival such as viral infections, andneurodegenerative diseases for example. PKB plays an important role inmaintaining the survival of immune cells during an immune response andtherefore PKB inhibitors could be particularly beneficial in immunedisorders including autoimmune conditions.

Therefore, the combinations could be useful in the treatment of diseasesin which there is a disorder of proliferation, apoptosis ordifferentiation.

The combinations may also be useful in diseases resulting from insulinresistance and insensitivity, and the disruption of glucose, energy andfat storage such as metabolic disease and obesity.

Examples of cancers which may be inhibited include, but are not limitedto, a carcinoma, for example a carcinoma of the bladder, breast, colon(e.g. colorectal carcinomas such as colon adenocarcinoma and colonadenoma), kidney, epidermal, liver, lung, for example adenocarcinoma,small cell lung cancer and non-small cell lung carcinomas, oesophagus,gall bladder, ovary, pancreas e.g. exocrine pancreatic carcinoma,stomach, cervix, endometrium, thyroid, prostate, or skin, for examplesquamous cell carcinoma; a hematopoletic tumour of lymphoid lineage, forexample leukaemia, acute lymphocytic leukaemia, B-cell lymphoma, T-celllymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy celllymphoma, or Burkett's lymphoma; a hematopoietic tumour of myeloidlineage, for example acute and chronic myelogenous leukaemias,myelodysplastic syndrome, or promyelocytic leukaemia; thyroid follicularcancer; a tumour of mesenchymal origin, for example fibrosarcoma orhabdomyosarcoma; a tumour of the central or peripheral nervous system,for example astrocytoma, neuroblastoma, glioma or schwannoma; melanoma;seminoma; teratocarcinoma; osteosarcoma; xenoderoma pigmentosum;keratoctanthoma; thyroid follicular cancer; or Kaposi's sarcoma.

Thus, in the pharmaceutical compositions, uses or methods of thisinvention for treating a disease or condition comprising abnormal cellgrowth, the disease or condition comprising abnormal cell growth in oneembodiment is a cancer.

Particular subsets of cancers include breast cancer, ovarian cancer,colon cancer, prostate cancer, oesophageal cancer, squamous cancer andnon-small cell lung carcinomas.

A further subset of cancers includes breast cancer, ovarian cancer,prostate cancer, endometrial cancer and glioma.

Immune Disorders

Immune disorders for which the combinations may be beneficial includebut are not limited to autoimmune conditions and chronic inflammatorydiseases, for example systemic lupus erythematosus, autoimmune mediatedglomerulonephritis, rheumatoid arthritis, psoriasis, inflammatory boweldisease, and autoimmune diabetes mellitus, Eczema hypersensitivityreactions, asthma, COPD, rhinitis, and upper respiratory tract disease.

Other Therapeutic Uses

PKB plays a role in apoptosis, proliferation, differentiation andtherefore the combinations could also be useful in the treatment of thefollowing diseases other than cancer and those associated with immunedysfunction; viral infections, for example herpes virus, pox virus,Epstein-Barr virus, Sindbis virus, adenovirus, HIV, HPV, HCV and HCMV;prevention of AIDS development in HIV-infected individuals;cardiovascular diseases for example cardiac hypertrophy, restenosis,atherosclerosis; neurodegenerative disorders, for example Alzheimer'sdisease, AIDS-related dementia, Parkinson's disease, amyotropic lateralsclerosis, retinitis pigmentosa, spinal muscular atropy and cerebellardegeneration; glomerulonephritis; myelodysplastic syndromes, ischemicinjury associated myocardial infarctions, stroke and reperfusion injury,degenerative diseases of the musculoskeletal system, for example,osteoporosis and arthritis, aspirin-sensitive rhinosinusitis, cysticfibrosis, multiple sclerosis, kidney diseases.

Methods of Treatment and Posology

A typical daily dose of the compound of formula (I) can be in the rangefrom 100 picograms to 100 milligrams per kilogram of body weight, moretypically 5 nanograms to 25 milligrams per kilogram of bodyweight, andmore usually 10 nanograms to 15 milligrams per kilogram (e.g. 10nanograms to 10 milligrams, and more typically 1 microgram per kilogramto 20 milligrams per kilogram, for example 1 microgram to 10 milligramsper kilogram) per kilogram of bodyweight although higher or lower dosesmay be administered where required. The compound of the formula (I) canbe administered on a daily basis or on a repeat basis every 2, or 3, or4, or 5, or 6, or 7, or 10 or 14, or 21, or 28 days for example.

The constituent compounds of the combinations of the invention may beadministered orally in a range of doses, for example 1 to 1500 mg, 2 to800 mg, or 5 to 500 mg, e.g. 2 to 200 mg or 10 to 1000 mg, particularexamples of doses including 10, 20, 50 and 80 mg. The compounds may beadministered once or more than once each day. The compounds can beadministered continuously (i.e. taken every day without a break for theduration of the treatment regimen). Alternatively, the compounds can beadministered intermittently, i.e. taken continuously for a given periodsuch as a week, then discontinued for a period such as a week and thentaken continuously for another period such as a week and so onthroughout the duration of the treatment regimen. Examples of treatmentregimens involving intermittent administration include regimens whereinadministration is in cycles of one week on, one week off; or two weekson, one week oft, or three weeks on, one week off; or two weeks on, twoweeks off; or four weeks on two weeks off; or one week on three weeksoff—for one or more cycles, e.g. 2, 3, 4, 5, 6, 7, 8, 9 or 10 or morecycles.

In another particular dosing schedule, a patient is given an infusionover 30 minutes to 1 hour followed by maintenance infusions of variableduration, for example 1 to 5 hours, e.g. 3 hours.

In a further particular dosing schedule, a patient is given a continuousinfusion for a period of 12 hours to 5 days, an in particular acontinuous infusion of 24 hours to 72 hours.

Ultimately, however, the quantity of compound administered and the typeof composition used will be commensurate with the nature of the diseaseor physiological condition being treated and will be at the discretionof the physician.

The combinations of the invention as defined herein can be furthercombined and/or administered with one of more other compounds fortreatment of a particular disease state, for example a neoplasticdisease such as a cancer as hereinbefore defined. Examples of othertherapeutic agents or treatments that may be administered together(whether concurrently or at different time intervals) with thecombinations of the invention include but are not limited to:

-   -   Topoisomerase I inhibitors    -   Antimetabolites    -   Tubulin targeting agents    -   DNA binder and topoisomerase II inhibitors    -   Alkylating Agents    -   Monoclonal Antibodies.    -   Anti-Hormones    -   Signal Transduction Inhibitors    -   Proteasome Inhibitors    -   DNA methyl transferases    -   Cytokines and retinoids    -   Chromatin targeted therapies    -   Radiotherapy, and,    -   Other therapeutic or prophylactic agents; for example agents        that reduce or alleviate some of the side effects associated        with chemotherapy. Particular examples of such agents include        anti-emetic agents and agents that prevent or decrease the        duration of chemotherapy-associated neutropenia and prevent        complications that arise from reduced levels of red blood cells        or white blood cells, for example erythropoietin (EPO),        granulocyte macrophage-colony stimulating factor (GM-CSF), and        granulocyte-colony stimulating factor (G-CSF). Also included are        agents that inhibit bone resorption such as bisphosphonate        agents e.g. zoledronate, pamidronate and ibandronate, agents        that suppress inflammatory responses (such as dexamethazone,        prednisone, and prednisolone) and agents used to reduce blood        levels of growth hormone and IGF-I in acromegaly patients such        as synthetic forms of the brain hormone somatostatin, which        includes octreotide acetate which is a long-acting octapeptide        with pharmacologic properties mimicking those of the natural        hormone somatostatin. Further included are agents such as        leucovorin, which is used as an antidote to drugs that decrease        levels of folic acid, or folinic acid it self and agents such as        megestrol acetate which can be used for the treatment of        side-effects including oedema and thromoembolic episodes.

For use in combination therapy with an ancillary compound, the compoundof the formula (I) and one, two, three, four or more ancillary compoundscan be, for example, formulated together in a dosage form containingtwo, three, four or more ancillary compounds. In an alternative, theconstituent compounds of the combination of the invention may beformulated separately and presented together in the form of a kit,optionally with instructions for their use.

It is envisaged that the combinations of the Invention will useful inthe prophylaxis or treatment of a range of disease states or conditionsmediated by protein kinase A and/or protein kinase B. Examples of suchdisease states and conditions are set out above.

The combinations of the invention are generally administered to asubject in need of such administration, for example a human or animalpatient, preferably a human.

The constituent compounds of the combination will typically beadministered in amounts that are therapeutically or prophylacticallyuseful and which generally are non-toxic. However, in certain situations(for example in the case of life threatening diseases), the benefits ofadministering the combination of the invention may outweigh thedisadvantages of any toxic effects or side effects, in which case it maybe considered desirable to administer the compound combination inamounts that are associated with a degree of toxicity.

The constituent compounds of the combinations of the invention may beadministered over a prolonged term to maintain beneficial therapeuticeffects or may be administered for a short period only. Alternativelythey may be administered in a pulsatile or continuous manner.

The compounds of the combination can be administered simultaneously orsequentially. When administered sequentially, they can be administeredat closely spaced intervals (for example over a period of 5-10 minutes)or at longer intervals (for example 1, 2, 3, 4 or more hours apart, oreven longer periods, e.g. 1, 2, 3, 4, 5, 6, or 7 days, apart whererequired), the precise dosage regimen being commensurate with theproperties of the therapeutic agent(s). With sequential administration,the delay in administering the second (or additional) active ingredientshould not be such as to lose the advantageous benefit of theefficacious effect of the combination of the active ingredients. Inaddition, the delay in administering the second (or additional) activeingredient is typically timed so as to allow for any adverse sideeffects of the first compound to subside to an acceptable level beforeadministration of the other compounds, whilst not losing theadvantageous benefit of the efficacious effect of the combination of theactive ingredients.

The two or more treatments may be given in individually varying doseschedules and via the same or different routes.

For example, one compound may be administered by the oral route and theother compound(s) administered by parenteral administration such asadministration by injection (e.g. i.v.) or infusion. In an alternative,all compounds may be administered by injection or infusion. In a furtheralternative, all compounds may be given orally. In one particularembodiment, the compound of the formula (I) is administered by injectionor infusion and one or more of the ancillary compound(s) areadministered orally.

When administered at different times, the administration of at least onecomponent of the combination may alternate with or interleaf withadministration of one or more of the other components or the componentsof the combination may be administered in sequential blocks of therapy.As indicated above, the administration of the components of thecombination may be spaced apart in time, for example by one or morehours, or days, or even weeks, provided that they form part of the sameoverall treatment.

In one embodiment of the invention, the compound of the formula (I) isadministered sequentially or simultaneously with the ancillarycompound(s).

In another embodiment of the invention, the compound of the formula (I)is administered sequentially with the ancillary compound(s) in eitherorder.

In a further embodiment, one or more of the ancillary compound(s) areadministered prior to the compound of the formula (I).

In another embodiment, one or more of the ancillary compound(s) areadministered after the compound of the formula (I).

In another embodiment of the invention, the compound of the formula (I)and one or more of the ancillary compound(s) are administeredsimultaneously.

In another embodiment, the compound of the formula (I) and the ancillarycompound(s) are each administered in a therapeutically effective amountwith respect to the individual components; in other words, the compoundof the formula (I) and the ancillary compound(s) are administered inamounts that would be therapeutically effective even if the componentswere administered other than in combination.

In another embodiment, the compound of the formula (I) and at least oneof the ancillary compound(s) are each administered in a sub-therapeuticamount with respect to the individual components; in other words, thecompound of the formula (I) and the ancillary compound are administeredin amounts that would be therapeutically ineffective if the componentswere administered other than in combination.

Preferably, the compound of the formula (I) and one or more of theancillary compound(s) interact in a synergistic or additive manner, andin particular an additive manner.

A typical daily dose of the compound of the formula (I) present in thecombination of the invention can be in the range from 100 picograms to100 milligrams per kilogram of body weight, typically 10 nanograms to 10milligrams per kilogram of bodyweight, more typically 1 microgram to 10milligrams although higher or lower doses may be administered whererequired. Each compound can be administered on a daily basis or on arepeat basis every 2, or 3, or 4, or 5, or 6, or 7, or 10 or 14, or 21,or 28 days for example.

In one particular dosing schedule, a patient will be given an infusionof a compound of the formula (I) for periods of one hour daily for up toten days in particular up to five days for one week, and the treatmentrepeated at a desired interval such as two to four weeks, in particularevery three weeks.

More particularly, a patient may be given an infusion of a compound ofthe formula (I) for periods of one hour daily for 5 days and thetreatment repeated every three weeks.

Accordingly, a person skilled in the art would know through their commongeneral knowledge the dosing regimes and combination therapies to use.It will be appreciated that the preferred method and order ofadministration and the respective dosage amounts and regimes for eachcomponent of the combination will depend on the particular ancillarycompound(s) and compound of Formula (I) being administered, their routeof administration, the particular tumour being treated and theparticular host being treated. The optimum method and order ofadministration and dosage amounts and regime can be readily determinedby those skilled in the art using conventional methods and in view ofthe information set out herein.

As described infra, the compounds of the formula (I) are administered incombination therapy with an ancillary compound (e.g. one, two or moreancillary compounds), for example in the treatment of a particulardisease state (for example a neoplastic disease such as a cancer ashereinbefore defined). Examples of suitable ancillary compounds that maybe used in the combinations of the invention are described in detailabove.

However, the combinations of the invention may also be further combinedwith other classes of therapeutic agents or treatments that may beadministered together (whether concurrently or at different timeintervals) with the combinations of the invention.

For example, the combinations within Group A (as set out above) may befurther combined with other classes of therapeutic agents or treatments,including (but not limited to):

-   -   Topoisomerase I inhibitors    -   Antimetabolites    -   Tubulin targeting agents    -   DNA binder and topoisomerase II inhibitors    -   Alkylating Agents    -   Anti-Hormones    -   Cytokines and retinoids    -   Monoclonal antibodies    -   Other therapeutic or prophylactic agents, for example agents        that reduce or alleviate some of the side effects associated        with chemotherapy. These include anti-emetic agents and agents        that prevent or decrease the duration of chemotherapy-associated        neutropenia and prevent complications that arise from reduced        levels of red blood cells or white blood cells, for example        erythropoietin (EPO), granulocyte macrophage-colony stimulating        factor (GM-CSF), leucovorin, granulocyte-colony stimulating        factor (G-CSF). Also included are agents that inhibit bone        resorption such as bisphosphonate agents e.g. zoledronate,        pamidronate and ibandronate, as well as agents that suppress        Inflammatory responses (such as dexamethazone).

In another embodiment, the combinations within Group B (as set outabove) may be further combined with other classes of therapeutic agentsor treatments, including (but not limited to):

-   -   Monoclonal Antibodies.    -   Anti-Hormones    -   Signal Transduction Inhibitors    -   Proteasome Inhibitors    -   DNA methyl transferases    -   Cytokines and retinoids    -   Other therapeutic or prophylactic agents, for example agents        that reduce or alleviate some of the side effects associated        with chemotherapy. These include anti-emetic agents and agents        that prevent or decrease the duration of chemotherapy-associated        neutropenia and prevent complications that arise from reduced        levels of red blood cells or white blood cells, for example        erythropoietin (EPO), granulocyte macrophage-colony stimulating        factor (GM-CSF), leucovorin, granulocyte-colony stimulating        factor (G-CSF). Also included are agents that Inhibit bone        resorption such as bisphosphonate agents e.g. zoledronate,        pamidronate and ibandronate, as well as agents that suppress        inflammatory responses (such as dexamethazone).

In another embodiment, the combinations within Group C (as set outabove) may be further combined with other classes of therapeutic agentsor treatments, including (but not limited to):

-   -   Topoisomerase I inhibitors    -   Antimetabolites    -   Tubulin targeting agents    -   DNA binder and topoisomerase II inhibitors    -   Alkylating Agents    -   Anti-Hormones    -   Signal Transduction Inhibitors    -   Proteasome Inhibitors    -   DNA methyl transferases    -   Cytokines and retinoids    -   Other therapeutic or prophylactic agents, for example agents        that reduce or alleviate some of the side effects associated        with chemotherapy. These include anti-emetic agents and agents        that prevent or decrease the duration of chemotherapy-associated        neutropenia and prevent complications that arise from reduced        levels of red blood cells or white blood cells, for example        erythropoietin (EPO), granulocyte macrophage-colony stimulating        factor (GM-CSF), leucovorin, granulocyte-colony stimulating        factor (G-CSF). Also included are agents that inhibit bone        resorption such as bisphosphonate agents e.g. zoledronate,        pamidronate and ibandronate, as well as agents that suppress        inflammatory responses (such as dexamethazone).

In another embodiment, the combinations within Group D (as set outabove) may be further combined with other classes of therapeutic agentsor treatments, including (but not limited to):

-   -   Topoisomerase I inhibitors    -   Antimetabolites    -   Tubulin targeting agents    -   DNA binder and topoisomerase II inhibitors    -   Alkylating Agents    -   Monoclonal Antibodies.    -   Signal Transduction Inhibitors    -   Proteasome Inhibitors    -   DNA methyl transferases    -   Other therapeutic or prophylactic agents, for example agents        that reduce or alleviate some of the side effects associated        with chemotherapy. These Include anti-emetic agents and agents        that prevent or decrease the duration of chemotherapy-associated        neutropenia and prevent complications that arise from reduced        levels of red blood cells or white blood cells, for example        erythropoietin (EPO), granulocyte macrophage-colony stimulating        factor (GM-CSF), leucovorin, granulocyte-colony stimulating        factor (G-CSF). Also included are agents that inhibit bone        resorption such as bisphosphonate agents e.g. zoledronate,        pamidronate and ibandronate, as well as agents that suppress        inflammatory responses (such as dexamethazone).

In another embodiment, the combinations within Group E (as set outabove) may be further combined with other classes of therapeutic agentsor treatments, including (but not limited to):

-   -   Topoisomerase I inhibitors    -   Antimetabolites    -   Tubulin targeting agents    -   DNA binder and topoisomerase II inhibitors    -   Alkylating Agents    -   Monoclonal Antibodies.    -   Anti-Hormones    -   Signal Transduction Inhibitors    -   Proteasome Inhibitors    -   DNA methyl transferases    -   Cytokines and retinoids        Other therapeutic or prophylactic agents, for example agents        that reduce or alleviate some of the side effects associated        with chemotherapy. These include anti-emetic agents and agents        that prevent or decrease the duration of chemotherapy-associated        neutropenia and prevent complications that arise from reduced        levels of red blood cells or white blood cells, for example        erythropoietin (EPO), granulocyte macrophage-colony stimulating        factor (GM-CSF), leucovorin, granulocyte-colony stimulating        factor (G-CSF). Also included are agents that inhibit bone        resorption such as bisphosphonate agents e.g. zoledronate,        pamidronate and ibandronate, as well as agents that suppress        inflammatory responses (such as dexamethazone).

Each of the compounds present in the combinations of the invention maybe given in individually varying dose schedules and via differentroutes.

Thus, administration of the compound of the formula (I) in combinationtherapy with an ancillary compound (e.g. one, two or more ancillarycompounds) may comprise simultaneous or sequential administration. Whenadministered sequentially, they can be administered at closely spacedintervals (for example over a period of 5-10 minutes) or at longerintervals (for example 1, 2, 3, 4 or more hours apart, or even longerperiods apart where required), the precise dosage regimen beingcommensurate with the properties of the therapeutic agent(s).

The combinations of the invention may also be administered inconjunction with non-chemotherapeutic treatments such as radiotherapy,photodynamic therapy, gene therapy, surgery and controlled diets.

The combination therapy may therefore involve the formulation of thecompound of the formula (I) with two, three, four or more othertherapeutic agents (including at least two ancillary compounds). Suchformulations can be, for example, a dosage form containing two, three,four or more therapeutic agents. In an alternative, the individualtherapeutic agents may be formulated separately and presented togetherin the form of a kit, optionally with instructions for their use.

A person skilled in the art would know through their common generalknowledge the dosing regimes and combination therapies to use.

Methods of Diagnosis

Prior to administration of the combination of the invention, a patientmay be screened to determine whether a disease or condition from whichthe patient is or may be suffering is one which would be susceptible totreatment with a compound of formula (I) and/or treatment with anancillary compound (e.g. one, two or more ancillary compounds).

For example, a biological sample taken from a patient may be analysed todetermine whether a condition or disease, such as cancer, that thepatient is or may be suffering from is one which is characterised by agenetic abnormality or abnormal protein expression which leads toup-regulation of PKA and/or PKB or to sensitisation of a pathway tonormal PKA and/or PKB activity, or to upregulation of a signaltransduction component upstream of PKA and/or PKB such as, in the caseof PKB, PI3K, GF receptor and PDK 1 & 2.

Alternatively, a biological sample taken from a patient may be analysedfor loss of a negative regulator or suppressor of the PKB pathway suchas PTEN. In the present context, the term “loss” embraces the deletionof a gene encoding the regulator or suppressor, the truncation of thegene (for example by mutation), the truncation of the transcribedproduct of the gene, or the inactivation of the transcribed product(e.g. by point mutation) or sequestration by another gene product.

The term up-regulation includes elevated expression or over-expression,including gene amplification (i.e. multiple gene copies) and increasedexpression by a transcriptional effect, and hyperactivity andactivation, including activation by mutations. Thus, the patient may besubjected to a diagnostic test to detect a marker characteristic ofup-regulation of PKA and/or PKB. The term diagnosis includes screening.By marker we include genetic markers including, for example, themeasurement of DNA composition to identify mutations of PKA and/or PKB.The term marker also includes markers which are characteristic of upregulation of PKA and/or PKB, including enzyme activity, enzyme levels,enzyme state (e.g. phosphorylated or not) and mRNA levels of theaforementioned proteins.

The above diagnostic tests and screens are typically conducted on abiological sample selected from tumour biopsy samples, blood samples(isolation and enrichment of shed tumour cells), stool biopsies, sputum,chromosome analysis, pleural fluid, peritoneal fluid, or urine.

Identification of an individual carrying a mutation in PKA and/or PKB ora rearrangement of TCL-1 or loss of PTEN expression may mean that thepatient would be particularly suitable for treatment with a PKA and/orPKB inhibitor. Tumours may preferentially be screened for presence of aPKA and/or PKB variant prior to treatment. The screening process willtypically involve direct sequencing, oligonucleotide microarrayanalysis, or a mutant specific antibody.

Methods of identification and analysis of mutations and up-regulation ofproteins are known to a person skilled in the art. Screening methodscould include, but are not limited to, standard methods such asreverse-transcriptase polymerase chain reaction (RT-PCR) or in-situhybridisation.

In screening by RT-PCR, the level of mRNA in the tumour is assessed bycreating a cDNA copy of the mRNA followed by amplification of the cDNAby PCR. Methods of PCR amplification, the selection of primers, andconditions for amplification, are known to a person skilled in the art.Nucleic acid manipulations and PCR are carried out by standard methods,as described for example in Ausubel, F. M. et al., eds. CurrentProtocols in Molecular Biology, 2004, John Wiley & Sons Inc., or Innis,M. A. et-al., eds. PCR Protocols: a guide to methods and applications,1990, Academic Press, San Diego. Reactions and manipulations involvingnucleic acid techniques are also described in Sambrook et al., 2001,3^(rd) Ed, Molecular Cloning: A Laboratory Manual, Cold Spring HarborLaboratory Press. Alternatively a commercially available kit for RT-PCR(for example Roche Molecular Biochemicals) may be used, or methodologyas set forth in U.S. Pat. Nos. 4,666,828; 4,683,202; 4,801,531;5,192,659, 5,272,057, 5,882,864, and 6,218,529 and incorporated hereinby reference.

An example of an in-situ hybridisation technique for assessing mRNAexpression would be fluorescence in-situ hybridisation (FISH) (seeAngerer, 1987 Meth. Enzymol., 152: 649).

Generally, in situ hybridization comprises the following major steps:(1) fixation of tissue to be analyzed; (2) prehybridization treatment ofthe sample to increase accessibility of target nucleic acid, and toreduce nonspecific binding; (3) hybridization of the mixture of nucleicacids to the nucleic acid in the biological structure or tissue; (4)post-hybridization washes to remove nucleic acid fragments not bound inthe hybridization, and (5) detection of the hybridized nucleic acidfragments. The probes used in such applications are typically labeled,for example, with radioisotopes or fluorescent reporters. Preferredprobes are sufficiently long, for example, from about 50, 100, or 200nucleotides to about 1000 or more nucleotides, to enable specifichybridization with the target nucleic acid(s) under stringentconditions. Standard methods for carrying out FISH are described inAusubel, F. M. et al., eds. Current Protocols in Molecular Biology,2004, John Wiley & Sons Inc and Fluorescence in Situ Hybridization:Technical Overview by John M. S. Bartlett in Molecular Diagnosis ofCancer, Methods and Protocols, 2nd ed.; ISBN: 1-59259-760-2; March 2004,pps. 077-088; Series: Methods in Molecular Medicine.

Alternatively, the protein products expressed from the mRNAs may beassayed by immunohistochemistry of tumour samples, solid phaseimmunoassay with microtitre plates, Western blotting, 2-dimensionalSDS-polyacrylamide gel electrophoresis, ELISA, flow cytometry and othermethods known in the art for detection of specific proteins. Detectionmethods would include the use of site specific antibodies. The skilledperson will recognize that all such well-known techniques for detectionof upregulation of PKB, or detection of PKB variants could be applicablein the present case.

Therefore all of these techniques could also be used to identify tumoursparticularly suitable for treatment with PKA and/or PKB inhibitors.

For example, as stated above, PKB beta has been found to be upregulatedin 10-40% of ovarian and pancreatic cancers (Bellacosa et at 1995, Int.J. Cancer 64, 280-285; Cheng et al 1996, PNAS 93, 3636-3641; Yuan et al2000, Oncogene 19, 2324-2330). Therefore it is envisaged that PKBinhibitors, and in particular inhibitors of PKB beta, may be used totreat ovarian and pancreatic cancers.

PKB alpha is amplified in human gastric, prostate and breast cancer(Staal 1987, PNAS 84, 5034-5037; Sun et al 2001, Am. J. Pathol. 159,431-437). Therefore it is envisaged that PKB inhibitors, and inparticular inhibitors of PKB alpha, may be used to treat human gastric,prostate and breast cancer.

Increased PKB gamma activity has been observed in steroid independentbreast and prostate cell lines (Nakatani et al 1999, J. Biol. Chem. 274,21528-21532). Therefore it is envisaged that PKB Inhibitors, and inparticular inhibitors of PKB gamma, may be used to treat steroidindependent breast and prostate cancers.

EXPERIMENTAL

The invention will now be illustrated, but not limited, by reference tothe specific embodiments described in the following procedures andexamples.

The starting materials for each of the procedures described below arecommercially available unless otherwise specified.

In the examples, the compounds prepared were characterised by liquidchromatography, mass spectroscopy and ¹H nuclear magnetic resonancespectroscopy using the systems and operating conditions set out below.

Proton magnetic resonance (¹H NMR) spectra were recorded on a BrukerAV400 instrument operating at 400.13 MHz, in Me-d₃-OD at 27 C, unlessotherwise stated and are reported as follows: chemical shift δ/ppm(number of protons, multiplicity where s=singlet, d=doublet, t=triplet,q=quartet, m=multiplet, br=broad). The residual protic solvent MeOH(δ_(H)=3.31 ppm) was used as the internal reference.

For the mass spectra, where chlorine is present, the mass quoted for thecompound is for ³⁵Cl.

In each of the examples, where the compounds are isolated or formed asthe free base, they can be converted into a salt form such as an aceticacid or hydrochloric acid salt. Conversely, where the compounds areisolated or formed as a salt, the salt can be converted into thecorresponding free base by methods well known to the skilled person, andthen optionally converted to another salt.

A number of liquid chromatography systems were used and these aredescribed below.

Platform System

HPLC System: Waters 2795 Mass Spec Detector: Micromass Platform LC PDADetector: Waters 2996 PDA

Acidic Analytical Conditions 1:

Eluent A: H₂O (0.1% Formic Acid) Eluent B: CH₃CN (0.1% Formic Acid)Gradient: 5-95% eluent B over 3.5 minutes Flow: 1.5 ml/min Column:Phenomenex Synergi 4μ Max-RP 80A, 50 × 4.6 mm

Acidic Analytical Conditions 2:

Eluent A: H₂O (0.1% Formic Acid) Eluent B: CH₃CN (0.1% Formic Acid)Gradient: 5-95% eluent B over 3.5 minutes Flow: 0.8 ml/min Column:Phenomenex Synergi 4μ Max-RP 80A, 50 × 2.0 mm

Acidic Analytical Conditions 3:

Eluent A: H₂O (0.1% Formic Acid) Eluent B: CH₃CN (0.1% Formic Acid)Gradient: 5-95% eluent B over 15 minutes Flow: 0.4 ml/min Column:Phenomenex Synergi 4μ Max-RP 80A, 50 × 2.0 mm

Basic Analytical Conditions 1:

Eluent A: H₂O (10 mM NH₄HCO₃ buffer adjusted to pH = 9.5 with NH₄OH)Eluent B: CH₃CN Gradient: 05-95% eluent B over 3.5 minutes Flow: 1.5ml/min Column: Waters XTerra MS C₁₈ 5 μm 4.6 × 50 mm

Basic Analytical Conditions 2:

Eluent A: H₂O (10 mM NH₄HCO₃ buffer adjusted to pH = 9.5 with NH₄OH)Eluent B: CH₃CN Gradient: 05-95% eluent B over 3.5 minutes Flow: 0.8ml/min Column: Thermo Hypersil-Keystone BetaBasic-18 5 μm, 50 × 2.1 mm

Basic Analytical Conditions 3:

Eluent A: H₂O (10 mM NH₄HCO₃ buffer adjusted to pH = 9.5 with NH₄OH)Eluent B: CH₃CN Gradient: 05-95% eluent B over 3.5 minutes Flow: 0.8ml/min Column: Phenomenex Luna C18(2) 5 μm, 50 × 2.0 mm

Basic Analytical Conditions 4:

Eluent A: H₂O (10 mM NH₄HCO₃ buffer adjusted to pH = 9.2 with NH₄OH)Eluent B: CH₃CN Gradient: 05-95% eluent B over 15 minutes Flow: 0.8ml/min Column: Phenomenex Luna C18(2) 5 μm, 150 × 2.0 mm

Polar Analytical Conditions:

Eluent A: H₂O (0.1% Formic Acid) Eluent B: CH₃CN (0.1% Formic Acid)Gradient: 00-50% eluent B over 3 minutes Flow: 1.5 ml/min Column:Phenomenex Synergi 4μ Hydro 80A, 50 × 4.6 mm

MS Conditions:

Capillary voltage: 3.5 kV or 3.6 kV Cone voltage: 30 V SourceTemperature: 120° C. Scan Range: 165-700 amu Ionisation Mode:ElectroSpray Negative, Positive or Positive & Negative

FractionLynx System

System: Waters FractionLynx (dual analytical/prep) HPLC Pump: Waters2525 Injector-Autosampler: Waters 2767 Mass Spec Detector:Waters-Micromass ZQ PDA Detector: Waters 2996 PDA

Acidic Analytical Conditions:

Eluent A: H₂O (0.1% Formic Acid) Eluent B: CH₃CN (0.1% Formic Acid)Gradient: 5-95% eluent B over 5 minutes Flow: 2.0 ml/min Column:Phenomenex Synergi 4μ Max-RP 80A, 50 × 4.6 mm

Polar Analytical Conditions:

Eluent A: H₂O (0.1% Formic Acid) Eluent B: CH₃CN (0.1% Formic Acid)Gradient: 00-50% eluent B over 5 minutes Flow: 2.0 ml/min Column:Phenomenex Synergi 4μ Max-RP 80A, 50 × 4.6 mm

MS Parameters for Acidic and Polar Analytical Conditions:

Capillary voltage: 3.5 kV Cone voltage: 25 V Source Temperature: 120° C.Scan Range: 125-800 amu Ionisation Mode: ElectroSpray Positive orElectroSpray Positive & Negative

Chiral Analytical Conditions:

Eluent: MeOH + 0.1% NH4/TFA Flow: 1.2 ml/min Total time: 16.00 min Inj.Volume: 10 μL Sample conc.: 2 mg/ml Column: Astec, Chirobiotic V; 250 ×4.6 mm

Mass spectrometer was taken off-line.

Agilent System

HPLC System: Agilent 1100 series Mass Spec Detector: Agilent LC/MSD VLMulti Wavelength Detector: Agilent 1100 series MWD Software: HPChemstation

Chiral Analytical Conditions:

Eluent: MeOH + 0.2% NH4/AcOH at room Temperature Flow: 2.0 ml/min Totaltime: 8.5 min Inj. Volume: 20 μL Sample Conc: 2 mg/ml Column: Astec,Chirobiotic V; 250 × 4.6 mm

Chiral Preparative Conditions 1:

Eluent: MeOH + 0.1% NH4/TFA at room Temperature Flow: 6.0 ml/min Totaltime: 10 min Inj. Volume: 100 μL Sample Conc: 20 mg/ml Column: Astec,Chirobiotic V; 250 × 10 mm

Chiral Preparative Conditions 2:

Eluent: MeOH + 0.2% NH4/AcOH at room Temperature Flow: 20.0 ml/min Totaltime: 19 min Inj. Volume: 950 μL Sample Conc: 25 mg/ml Column: Astec,Chirobiotic V2; 250 × 21.2 mm

MS Conditions (Lust Analytical Method):

Capillary voltage: 3000 V Fragmentor: 150 Gain: 1.00 Drying gas: 12.0L/min Drying gas T: 350° C. Nebulizer pressure: 35 (psig) Scan Range:125-800 amu Ionisation Mode: ElectroSpray Positive

In the examples below, the following key is used to identify the LCMSconditions used:

PS-A Platform System—acidic analytical conditions 1

PS-A2 Platform System—acidic analytical conditions 2

PS-A3 Platform System—acidic analytical conditions 3

PS-B Platform System—basic analytical conditions 1

PS-B2 Platform System—basic analytical conditions 2

PS-B3 Platform System—basic analytical conditions 3

PS-B4 Platform System—basic analytical conditions 4

PS-P Platform System—polar analytical conditions

FL-A FractionLynx System—acidic analytical conditions

FL-P FractionLynx System—polar analytical conditions

FL-C FractionLynx System—chiral analytical conditions

AG-CA Agilent System—chiral analytical conditions

AG-CP1 Agilent System—chiral preparative conditions 1

AG-CP2 Agilent System—chiral preparative conditions 2

Example 1 2-Phenyl-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethylamine

To a suspension of 2-(4-chlorophenyl)-2-phenylethylamine hydrochloride(134 mg, 0.5 mmol, 1.0 equiv.) (Array PPA-Q02-1) in toluene (0.8 ml) wasadded bis(tri-t-butylphosphine)palladium (0) (3 mg, 1 mol %) (Strem) andthe mixture was purged with nitrogen. A suspension of4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (107 mg,0.55 mmol, 1.1 equiv.) (Aldrich 52,505-7) in ethanol (0.8 ml) was addedfollowed by potassium carbonate (415 mg, 3.0 mmol, 6 equiv.) in water(2.5 ml). The mixture was purged with nitrogen and sealed. The reactionmixture was heated in a CEM Explorer™ microwave to 135° C. for 15minutes using 50 watts power. The solvents were removed and the residuewas partitioned between ethyl acetate and 2N NaOH. The aqueous layer wasextracted with ethyl acetate and the combined organic layers were washedwith brine, dried (MgSO₄) and concentrated under reduced pressure. Thecrude reaction mixture was purified by column chromatography (SiO₂),eluting with a mixture of dichloromethane (90 ml):methanol (18ml):acetic acid (3 ml):H₂O (2 ml) to afford the title compound 14 mg(9%); LCMS (PS-A) R_(t) 1.79 min; m/z [M+H]⁺ 264.

Example 2 3-Phenyl-2-[3-(1H-pyrazol-4-yl)-phenyl]-propionitrile 2A.2-(3-Bromo-phenyl)-3-phenyl-propionitrile

A solution of 40% KOH (2.83 g in 5.0 ml of H₂O) in ethanol (13 ml) wasadded to a solution of benzaldehyde (2.85 ml, 28.05 mmol) and3-bromophenylacetonitrile (5 g, 25.50 mmol) in ethanol (9 ml). Thereaction mixture was then stirred at room temperature for 2 hours andthe precipitate was collected by suction filtration and washed with coldethanol (6.68 g, 92%). The crude product (3.45 g, 12.14 mmol) was thendissolved in ethanol (35 ml) and heated to 65° C. Sodium borohydride(459 mg, 12.14 mmol) was added in portions and the reaction mixture wasmaintained at this temperature for a further 2 hours. Upon cooling,water (10 ml) was added and the solvent was removed under reducedpressure. The residue was partitioned between water (100 ml) and ethylacetate (100 ml). The organic layer was separated, dried (MgSO₄),filtered and concentrated to afford the desired product (1.80 g, 52%),which was used without purification.

2B. 3-Phenyl-2-[3-(1H-pyrazol-4-yl)-phenyl]-propionitrile

2-(3-Bromo-phenyl)-3-phenyl-propionitrile was reacted with4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole followingthe procedure set out in Example 1 to give the title compound. (LC/MS:(PS-A) R_(t) 2.98 [M+H]⁺ 274).

Example 32-[4-(3,5-Dimethyl-1H-pyrazol-4-yl)-phenyl]-2-phenyl-ethylamine

Following the procedure of Example 1 but using3,5-dimethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole(Boron Molecular D03-BM152) instead of4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole gave thetitle compound. (LC/MS: (PS-A) R_(t) 1.79 [M+H]⁺ 292.

Example 4 2-(4-Chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethylamine

Following the procedure of Example 1 but using2,2-bis-(4-chloro-phenyl)-ethylamine in place of2-(4-chlorophenyl)-2-phenylethylamine hydrochloride* gave the titlecompound. (LC/MS: (PS-A) R_(t) 1.99 [M+H]⁺ 298).

*This starting material can be made by the method described in J. Amer.Chem. Soc., 1983, 105, 3183-3188.

Example 52-[3-(3,5-Dimethyl-1H-pyrazol-4-yl)-phenyl]-1-phenyl-ethylamine 5A.2-(3-Bromo-phenyl)-1-phenyl-ethylamine

Benzonitrile (500 mg, 4.849 mmol) was added dropwise to a solution of3-bromobenzylmagnesium bromide (0.275 M solution in diethyl ether, 21.1ml, 5.818 mmol) under an atmosphere of nitrogen at room temperature. Thereaction mixture was then heated to reflux for a period of 2 hours thenallowed to cool. Lithium aluminium hydride (1.0 M in THF, 4.85 ml, 4.849mmol) was then added cautiously and the reaction mixture was allowed toheat at reflux for a further 16 hours. Upon cooling, the reaction wasquenched by cautious and dropwise addition of water (5 ml) and thenpartitioned between water (20 ml) and ethyl acetate (100 ml). Theorganic layer was separated, dried (MgSO₄), filtered and concentrated.Purification by ion exchange chromatography afforded the desiredcompound (420 mg, 31%).

5B. 2-[3-(3,5-Dimethyl-1H-pyrazol-4-yl)-phenyl]-1-phenyl-ethylamine

The product of 5B was reacted with3,5-dimethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazolefollowing the procedure set out in Example 1 to give the title compound.(LC/MS: (PS-B) R_(t) 2.54 [M+H]⁺ 292).

Example 6 3-Phenyl-2-[3-(1H-pyrazol-4-yl)-phenyl]-propylamine

To a solution of the product of Example 2 (70 mg, 0.256 mmol, 1.0 equiv)in ethanol (25 ml) was added concentrated ammonia (0.5 ml) and RaneyNickel (approximately 0.5 ml of the water suspension) and the reactionmixture was subjected to a hydrogen atmosphere for 17 hours. The mixturewas filtered through Celite® and the mother liquor was concentratedunder reduced pressure to give the title compound which was purified bypreparative liquid chromatography. (LC/MS: (PS-A) R_(t) 1.89 [M+H]⁺ 278.

Example 7 3-Phenyl-2-[4-(1H-pyrazol-4-yl)-phenyl]-propylamine 7A.2-(4-Bromo-phenyl)-3-phenyl-propionitrile

Following the procedure described in Example 2A but substituting4-bromophenylacetonitrile for 3-bromophenylacetonitrile gave the titlecompound was obtained which was used in the next step without furtherpurification.

7B. 3-Phenyl-2-[4-(1H-pyrazol-4-yl)-phenyl]-propionitrile

By following the procedure described in Example 1 but substituting2-(4-Bromo-phenyl)-3-phenyl-propionitrile for2-(4-chlorophenyl)-2-phenylethylamine, the title compound was obtained.

7C. 3-Phenyl-2-[4-(1H-pyrazol-4-yl)-phenyl]-propylamine

The nitrile product of Example 7B was reduced using the conditionsdescribed in Example 6 to give the title compound. (LC/MS: (PS-B) R_(t)3.03 [M+H]⁺ 278.

Example 8{3-(4-Chloro-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propyl}-methyl-amine8A. 3-(4-Bromo-phenyl)-2-cyano-acrylic acid ethyl ester

(J. Med. Chem, 1983, 26, 935-947)

4-Bromobenzaldehyde (3 g, 16.21 mmol) and ethyl cyanoacetate (1.9 ml,17.84 mmol) in toluene was added piperidine (27 μl) and the reactionmixture was refluxed for 1 hour with a Dean-Stark separator. The solventwas removed under reduced pressure, the residue triturated with warmethyl acetate, filtered to yield the desired product as a yellow solid(4.03 g, 89% yield). LC/MS: (PS-A2) R_(t) 3.44.

8B. 3-(4-Bromo-phenyl)-3-(4-chloro-phenyl)-2-cyano-propionic acid ethylester

A solution of 3-(4-bromo-phenyl)-2-cyano-acrylic acid ethyl ester (1.5g, 5.36 mmol) in dry toluene (12 ml) was added dropwise to4-chlorophenylmagnesium bromide (0.5 M solution in tetrahydrofuran, 6.96ml, 6.96 mmol) at 0° C. The reaction mixture was heated to 85° C. for 3hours, poured onto ice, acidified with 1N HCl and extracted with ethylacetate. The organic layer was separated, dried (MgSO₄), filtered andconcentrated, the crude product was purified over flash silicachromatography eluting with petroleum ether to ethyl acetate/petroleumether (5:95) to afford the desired product (1.91 g, 91% yield). LC/MS:(PS-A2) R_(t) 3.78 [M+H]⁺ 391.93.

8C. 3-(4-Bromo-phenyl)-3-(4-chloro-phenyl)-propionic acid

A mixture of 3-(4-bromo-phenyl)-3-(4-chloro-phenyl)-2-cyano-propionicacid ethyl ester (1.91, 4.87 mmol), acetic acid (10 ml), concentratedsulfuric acid (5 ml) and water (5 ml) were refluxed for 2 hours.Reaction mixture was poured into iced water and extracted with ethylacetate. The organic layer was separated, dried (MgSO₄), filtered andconcentrated, the crude product was purified over flash silicachromatography eluting with ethyl acetate/petroleum ether (1:1) toafford the desired product (0.82 g, 50% yield). LC/MS: (PS-A2) R_(t)3.39 [M+H]⁺ 338.86.

8D. 3-(4-Bromo-phenyl)-3-(4-chloro-phenyl)-N-methyl-propionamide

A mixture of 3-(4-bromo-phenyl)-3-(4-chloro-phenyl)-propionic acid (0.25g, 0.74 mmol) and 1-hydroxybenatriazole (0.12 g, 0.88 mmol) indichloromethane (3 ml) was stirred for 15 minutes before addition ofmethylamine (40% solution in water, 0.110, 1.47 mmol) and1-(3-dimethylaminopropyl)-ethylcarbodiimide hydrochloride (0.17 g, 0.88mmol). The reaction mixture was stirred for 16 hours, solvent removedunder reduced pressure and the residue partitioned between ethyl acetateand 1N HCl. The organic layer was separated, washed with saturatedsodium hydrogen carbonate, brine, dried (MgSO₄), filtered andconcentrated to yield the title compound which was used in the next stepwithout further purification. LC/MS: (PS-A2) R_(t) 3.20 [M+H]⁺ 353.95.

8E. [3-(4-Bromo-phenyl)-3-(4-chloro-phenyl)-propyl]-methyl-amine

Under a nitrogen atmosphere, the crude3-(4-bromo-phenyl)-3-(4-chloro-phenyl)-N-methyl-propionamide was cooledto 0° C., lithium aluminum hydride (0.075 g, 1.97 mmol) and diethylether (3 ml) were added. With cooling, aluminum chloride (0.23 g, 1.69mmol) was dissolved in diethyl ether (2 ml) and added. The reactionmixture was stirred for 16 hours, quenched with addition of water,basified (2N NaOH) and extracted with ethyl acetate. The organic layerwas separated, dried (MgSO₄), filtered and concentrated, the crudeproduct was purified over Phenomenex_Strata_SCX column chromatographyeluting with methanol followed by 2N ammonia in methanol to afford thedesired product (0.254 g, 62% yield for steps 1D and 1E combined).LC/MS: (PS-B3) R_(t) 3.20 [M+H]⁺ 339.85.

8F.{3-(4-Chloro-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propyl}-methyl-amine

[3-(4-Bromo-phenyl)-3-(4-chloro-phenyl)-propyl]-methyl-amine was reactedwith 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolefollowing the procedure set out in Example 1 to give the title compound.LC/MS: (PS-B3) R_(t) 2.63 [M+H]⁺ 326.00. ¹H NMR (Me-d₃-OD) δ 2.37-2.47(2H, m), 2.66 (3H, s), 2.91 (2H, t), 4.05 (1H, t), 7.25-7.34 (6H, m),7.54 (2H, d), 7.92 (2H, s), 8.51 (1H, br s—due to formic acid).

Example 9{3-(3,4-Difluoro-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propyl}-methyl-amine9A. 3-[4-Bromo-phenyl]-3-(3,4-difluoro-phenyl)-N-methyl-propionamide

By following the procedure described in Example 8A through to Example 8Cbut substituting 4-chlorophenylmagnesium bromide for3,4-difluorophenylmagnesium bromide, the title compound was obtained.LC/MS: (PS-A2) R_(t) 3.12 [M+H]⁺ 355.84.

9B.3-(3,4-Difluoro-phenyl)-N-methyl-3-[4-(1H-pyrazol-4-yl)-phenyl]-propionamide

3-(4-Bromo-phenyl)-3-(3,4-difluoro-phenyl)-N-methyl-propionamide wasreacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolefollowing the procedure set out in Example 1 to give the title compound.LC/MS: (PS-A2) R_(t) 2.55 [M+H]⁺ 341.93.

9C.{3-(3,4-Difluoro-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propyl}-methyl-amine

Lithium aluminium hydride was added to a suspension of3-(3,4-Difluoro-phenyl)-N-methyl-3-[4-(1H-pyrazol-4-yl)-phenyl]-propionamidein diethyl ether, followed by a solution of aluminium chloride indiethyl ether at 0° C., under a nitrogen atmosphere. Toluene was addedand the reaction mixture was heated at 70° C. for 18 hours. Upon coolingthe reaction was quenched with addition of water, basified (2N NaOH) andextracted with ethyl acetate. The organic layer was separated, dried(MgSO₄), filtered and concentrated to afford the desired compound.LC/MS: (PS-A2) R_(t) 2.15 [M+H]⁺ 328.06. ¹H NMR (Me-d₃-OD) δ 2.19-2.29(2H, m), 2.35 (3H, s), 2.51 (2H, t), 4.00 (1H, t), 7.06-7.24 (3H, m),7.27 (2H, d), 7.52 (2H, d), 7.92 (2H, s).

Example 10{3-(3-Chloro-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propyl}-methyl-amine

By following the procedure described in Example 8 but substituting4-chlorophenylmagnesium bromide for 3-chlorophenylmagnesium bromide, thetitle compound was obtained. LC/MS: (PS-B3) R_(t) 2.67 [M+H]⁺ 326.00. ¹HNMR (Me-d₃-OD) δ 2.43-2.50 (2H, m), 2.68 (3H, s), 2.94 (2H, m), 4.13(1H, t), 7.24 (1H, m), 7.27-7.36 (3H, m), 7.41 (2H, d), 7.66 (2H, d),8.50 (2H, s).

Example 113-(4-Chloro-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propionamide

By following the procedure described in Example 9A and 9B butsubstituting 3,4-difluorophenylmagnesium bromide for4-chlorophenylmagnesium bromide, the title compound was obtained. LC/MS:(PS-A2) R_(t) 2.54 [M+H]⁺ 326. ¹H NMR (Me-d₃-OD) δ 2.95 (2H, d), 4.53(1H, t), 7.27 (6H, m), 7.50 (2H, d), 7.91 (2H, s).

Example 123-(4-Chloro-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propylamine 12A.3-(4-Bromo-phenyl)-3-(4-chloro-phenyl)-propionamide

A solution of 3-(4-Bromo-phenyl)-3-(4-chloro-phenyl)-propionic acid*(0.25 g, 0.74 mmol) and 1,1′-carbonyldiimidazole (0.249, 1.47 mmol) indichloromethane was stirred for 45 minutes before the addition ofammonia (2M solution in methanol, 3.68 ml, 7.36 mmol). The reactionmixture was stirred for 2 hours, solvent removed under reduced pressureand residue was purified over flash silica chromatography eluting withethyl acetate/petroleum ether (1:4) to afford the title compound (0.091g, 36% yield). LC/MS: (PS-A2) R_(t) 3.08 [M+H]⁺ 339.93.

*This starting material can be made by the method described in Example8A through to 8C.

12B. 3-(4-Bromo-phenyl)-3-(4-chloro-phenyl)-propylamine

By following the procedure described in Example 8E but substituting3-(4-Bromo-phenyl)-3-(4-chloro-phenyl)-propionamide for3-(4-Bromo-phenyl)-3-(4-chloro-phenyl)-N-methyl-propionamide, the titlecompound was obtained. LC/MS: (PS-B2) R_(t) 3.88 [M+H]⁺ 359.87.

12C. 3-(4-Chloro-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propylamine

3-(4-Bromo-phenyl)-3-(4-chloro-phenyl)-propylamine was reacted with4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole followingthe procedure set out in Example 1 to give the title compound. LC/MS:(PS-B3) R_(t) 2.54 [M+H]⁺ 312.04. ¹H NMR (Me-d₃-OD) δ 2.39 (2H, m), 2.84(2H, t), 4.06 (1H, t), 7.27-7.33 (6H, m), 7.54 (2H, d), 7.91 (2H, s).

Example 133-(3,4-Dichloro-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propylamine

By following the procedure described in Example 12 but substituting4-chiorophenylmagnesium bromide for 3,4-dichlorophenylmagnesium bromide,the title compound was obtained. LC/MS: (PS-A2) R_(t) 2.17 [M+H]⁺345.95. ¹H NMR (Me-d₃-OD) δ 2.39 (2H, m), 2.84 (2H, t), 4.07 (1H, t),7.24-7.31 (4H, m), 7.45-7.49 (2H, m), 7.56 (2H, d), 7.93 (2H, s).

Example 14 4-(4-Chloro-phenyl)-4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidine14A. 4-(4-Bromo-phenyl)-4-(4-chloro-phenyl)-piperidine

A suspension of 4-(4-Bromo-phenyl)-piperidin-4-ol (4.02 g, 15.7 mmol) inchlorobenzene (30 ml) was added dropwise to a suspension of aluminiumchloride (7.32 g, 54.9 mmol) in chlorobenzene (10 ml) at 0° C. Thereaction mixture was stirred at 0° C. for 2 hours, quenched by additionof ice then methyl t-butyl ether added. After stirring for 1 hour theprecipitate was collected by filtration washed with water, methylt-butyl ether and water to afford the title compound (5.59 g, 92%yield). LC/MS: (PS-B3) R_(t) 3.57 [M+H]⁺ 350, 352.

14B. 4-(4-Chloro-phenyl)-4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidine

4-(4-Bromo-phenyl)-4-(4-chloro-phenyl)-piperidine was reacted with4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole followingthe procedure set out in Example 1 to give the title compound. LC/MS:(PS-A3) R_(t) 7.22 [M+H]⁺ 338.08. ¹H NMR (Me-d₃-OD) δ 2.64-2.74 (4H, m),3.22-3.25 (4H, m), 7.33-7.45 (6H, m), 7.65 (2H, d), 8.37 (2H, s).

Example 154-(4-Methoxy-phenyl)-4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidine

By following the procedure described in Example 14 but substitutingchlorobenzene for anisole, the title compound was obtained. LC/MS:(PS-B3) R_(t) 2.42 [M+H]⁺ 334.00. ¹H NMR (Me-d₃-OD) δ 2.69 (4H, m), 3.23(4H, m), 3.76 (3H, s), 6.90 (2H, d), 7.28 (2H, d), 7.40 (2H, d), 7.65(2H, d), 8.53 (2H, s).

Example 164-(4-Chloro-phenyl)-1-methyl-4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidine16A. 4-(4-Bromo-phenyl)-4-(4-chloro-phenyl)-piperidine-1-carboxylic acidethyl ester

To a stirring suspension of4-(4-Bromo-phenyl)-4-(4-chloro-phenyl)-piperidine* (0.28 g, 0.80 mmol)in dichloromethane (10 ml), were added triethylamine (0.45 ml, 3.2 mmol)and ethyl chloroformate (0.085 ml, 0.88 mmol). The reaction mixture wasstirred for 3 hours, diluted with ethyl acetate and washed with 1N HCl,saturated sodium hydrogen carbonate and brine. The organic layer wasseparated, dried (MgSO₄), filtered and concentrated to afford the titlecompound (0.29 g, 94% yield). LCMS: (PS-A2), R_(t) 4.02 [M+H]⁺ 422, 424.

*This starting material can be made by the method described in Example14A

16B. 4-(4-Bromo-phenyl)-4-(4-chloro-phenyl)-1-methyl-piperidine

Under a nitrogen atmosphere4-(4-Bromo-phenyl)-4-(4-chloro-phenyl)-piperidine-1-carboxylic acidethyl ester (0.28 g, 0.66 mmol) and lithium aluminum hydride (0.051 g)were suspended in tetrahydrofuran (5 ml) and stirred for 2 hours. Thereaction mixture was quenched with addition of water, solvent removedunder reduced pressure, the residue was partitioned between ethylacetate and 2N NaOH. The organic layer was washed with brine, dried(MgSO₄), filtered and concentrated to afford the desired product (0.241g, 99% yield). LC/MS: (PS-B3) R_(t) 3.78 [M+H]⁺ 363.95, 365.73,

16C.4-(4-Chloro-phenyl)-1-methyl-4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidine

4-(4-Bromo-phenyl)-4-(4-chloro-phenyl)-1-methyl-piperidine was reactedwith 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolefollowing the procedure set out in Example 1 to give the title compound.LC/MS: (PS-B3) R_(t) 2.90 [M+H]⁺ 352. ¹H NMR (Me-d₃-OD) δ 2.41-2.53 (2H,m), 2.82 (3H, d), 2.97-3.12 (4H, m), 3.56-3.59 (2H, m), 7.28 (2H, s),7.34 (1H, m), 7.42 (1H, d), 7.49 (1H, d), 7.54 (1H, d), 7.61 (1H, d),7.75 (1H, d), 8.52 (2H, d).

Example 17 4-Phenyl-4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidine

By following the procedure described in Example 1 but substituting2-(4-chlorophenyl)-2-phenylethylamine hydrochloride for4-(4-Chloro-phenyl)-4-phenyl-piperidine, the title compound wasobtained. LC/MS: (PS-A2) R_(t) 1.88 [M+H]⁺ 304. ¹H NMR (Me-d₃-OD) δ2.65-2.71 (4H, m), 3.21 (4H, t), 7.18-7.22 (1H, m), 7.32-7.38 (6H, m),7.55 (2H, d), 7.93 (2H, s).

Example 184-[4-(3,5-Dimethyl-1H-pyrazol-4-yl)-phenyl]-4-phenyl-piperidine

By following the procedure described in Example 1 but substituting2-(4-chlorophenyl)-2-phenylethylamine hydrochloride and4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole for4-(4-chloro-phenyl)-4-phenyl-piperidine and3,5-dimethyl-4-(4,4,5,6-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole,the title compound was obtained. LC/MS: (PS-A2) R_(t) 2.95 [M+H]⁺ 315.¹H NMR (Me-d₃-OD) δ 2.22 (6H, s), 2.66-2.76 (4H, m), 3.16-3.28 (4H, m),7.19-7.44 (9H, m).

Example 19Dimethyl-{3-[4-(1H-pyrazol-4-yl)-phenyl]-3-pyridin-2-yl-propyl}-amine

By following the procedure described in Example 1 but substituting2-(4-chlorophenyl)-2-phenylethylamine hydrochloride for brompheniraminemaleate, the title compound was obtained. LC/MS: (PS-B2) R_(t) 2.29[M+H]⁺ 307. ¹H NMR (Me-d₃-OD) δ 2.44-2.54 (1H, m), 2.59-2.70 (1H, m),2.77 (6H, s), 2.93-3.01 (2H, m), 4.20 (1H, t), 7.25-7.28 (1H, m),7.32-7.36 (3H, m), 7.54 (2H, d), 7.75 (1H, dt), 7.94 (2H, br s).

Example 20{2-(4-Chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-dimethyl-amine20A. 2,2-Bis-(4-chloro-phenyl)-N,N-dimethyl-acetamide

Bis-(4-chloro-phenyl)-acetic acid was reacted with dimethylaminefollowing the procedure set out in Example 8D to give the titlecompound. LC/MS: (PS-A2) R_(t) 3.40 [M+H]⁺ 309.95.

20B. [2,2-Bis-(4-chloro-phenyl)-ethyl]-dimethyl-amine

By following the procedure described in Example 8E but substituting3-(4-Bromo-phenyl)-3-(4-chloro-phenyl)-N-methyl-propionamide for2,2-Bis-(4-chloro-phenyl)-N,N-dimethyl-acetamide, the title compound wasobtained. LC/MS: (PS-B2) R_(t) 3.75 [M+H]⁺ 295.99.

20C.{2-(4-Chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-dimethyl-amine

[2,2-Bis-(4-chloro-phenyl)-ethyl]-dimethyl-amine was reacted with4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole followingthe procedure set out in Example 1 to give the title compound. LC/MS:(PS-B2) R_(t) 3.07 [M+H]⁺ 325.99. ¹H NMR (Me-d₃-OD) δ 2.5 (6H, s), 2.98(2H, dd), 4.34 (1H, t), 7.31-7.36 (6H, m), 7.50 (2H, d), 7.92 (2H, s).

Example 21{2-(4-Chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-methyl-amine

By following the procedure described in Example 20 but substitutingdimethylamine for methylamine, the title compound was obtained. LC/MS:(PS-B2) R_(t) 2.83 [M+H]⁺ 312.07. ¹H NMR (Me-d₃-OD) δ 2.42 (3H, s),3.20-3.23 (2H, dd), 4.18 (1H, t), 7.27-7.33 (6H, m), 7.54 (2H, d), 7.92(2H, br s).

Example 22{2-(4-Chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-methyl-amine(R)

Prepared using the same procedure as Example 21 but enantiomersseparated by chiral preparative HPLC using method AG-CP2. LCMS: (AG-CA)R_(t) 5.58 min, 97.4% ee. ¹H NMR (Me-d₃-OD) δ 2.75 (3H, s), 3.78 (2H,d), 4.43 (1H, t), 7.39 (4H, s), 7.44 (2H, d), 7.69 (2H, d), 8.43 (2H,s).

Example 23{2-(4-Chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-methyl-amine(S)

Prepared using the same procedure as Example 21 but enantiomersseparated by chiral preparative HPLC using method AG-CP2. LCMS: (AG-CA)R_(t) 4.51 min, 98.0% ee. ¹H NMR (Me-d₃-OD) δ 2.75 (3H, s), 3.79 (2H,d), 4.51 (1H, t), 7.37-7.43 (4H, m), 7.49 (2H, d), 7.73 (2H, d), 8.66(2H, s).

Example 244-{2-(4-Chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-morpholine

By following the procedure described in Example 20 but substitutingdimethylamine for morpholine, the title compound was obtained. LC/MS:(PS-B3) R_(t) 3.07 [M+H]⁺ 368.05. ¹H NMR (Me-d₃-OD) δ 2.50 (4H, m), 2.97(2H, m), 3.60 (4H, t), 4.26 (1H, t), 7.27 (6H, m). 7.49 (2H, d), 7.89(2H, s).

Example 254-{4-[1-(4-Chloro-phenyl)-2-pyrrolidin-1-yl-ethyl]-phenyl}-1H-pyrazole

By following the procedure described in Example 20 but substitutingdimethylamine for pyrrolidine, the title compound was obtained. LC/MS:(PS-A2) R_(t) 2.06 [M+H]⁺ 354.01. ¹H NMR (Me-d₃-OD) δ 1.85 (4H, m), 2.87(4H, m), 3.47 (2H, d), 4.31 (1H, t), 7.30-7.37 (6H, m), 7.54 (2H, d),7.92 (2H, s).

Example 26{2-(4-Chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-isopropyl-amine

By following the procedure described in Example 20 but substitutingdimethylamine for isopropylamine, the title compound was obtained.LC/MS: (PS-A2) R_(t) 2.10 [M+H]⁺ 340. ¹H NMR (Me-d₃-OD) δ 1.31 (6H, d),3.38-3.45 (1H, m), 3.65-3.74 (2H, m), 4.39 (1H, br t), 7.37 (6H, m),7.59 (2H, d), 7.94 (2H, s).

Example 27Dimethyl-{2-phenyl-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-amine

By following the procedure described in Example 20, the title compoundwas obtained. LC/MS: (PS-B2) R_(t) 2.82 [M+H]⁺ 292.11. ¹H NMR (Me-d₃-OD)δ 2.25 (6H, s), 2.95-3.04 (2H, m), 4.20 (1H, t), 7.16 (1H, t), 7.26-7.33(6H, m), 7.49 (2H, d), 7.89 (2H, s).

Example 28 {2,2-Bis-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-dimethyl-amine

By following the procedure described in Example 20, the title compoundwas obtained. LC/MS: (PS-B2) R_(t) 2.45 [M+H]⁺ 358.11. ¹H NMR (Me-d₃-OD)δ 2.69 (6H, s), 3.59 (2H, d), 4.43 (1H, t), 7.39 (4H, d), 7.57 (4H, d),7.93 (4H, s).

Example 29 {2,2-Bis-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-methyl-amine

By following the procedure described in Example 21, the title compoundwas obtained. LC/MS: (PS-B2) R_(t) 2.18 [M+H]⁺ 344.11. ¹H NMR (Me-d₃-OD)δ 2.65 (3H, s), 3.60 (2H, d), 4.34 (1H, t), 7.36 (4H, d), 7.59 (4H, d),7.94 (4H, s).

Example 30 2-(4-Chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethylamine(R)

Prepared using the same procedure as Example 4 but enantiomers separatedby chiral preparative HPLC using method AG-CP1. LCMS: (FL-C) R_(t) 10.97min, 95.7% ee. ¹H NMR (Me-d₃-OD) δ 3.65 (2H, m), 4.30 (1H, t), 7.35-7.40(6H, m), 7.64 (2H, d), 8.16 (2H, s).

Example 31 2-(4-Chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethylamine(S)

Prepared using the same procedure as Example 4 but enantiomers separatedby chiral preparative HPLC using method AG-CP1. LCMS: (FL-C) R_(t) 9.63min, 100% ee. ¹H NMR (Me-d₃-OD) δ 3.66 (2H, m), 4.30 (1H, t), 7.35-7.40(6H, m), 7.64 (2H, d), 8.15 (2H, s).

Example 32 2-(4-Chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-acetamide

By following the procedure described in Example 12A followed by 12C butsubstituting 3-(4-Bromo-phenyl)-3-(4-chloro-phenyl)-propionic acid forBis-(4-chloro-phenyl)-acetic acid, the title compound was obtained.LC/MS: (PS-A2) R_(t) 2.53 [M+H]⁺ 312. ¹H NMR (Me-d₃-OD) δ 4.99 (1H, s),7.30-7.33 (6H, m), 7.55 (2H, d), 7.86-8.02 (2H, br s).

Example 331-{2-(4-Chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-piperazine37A. Bis-(4-chloro-phenyl)-acetaldehyde

Dess-Martin periodinane (3.17 g, 7.49 mmol) was added to a solution of2,2-Bis-(4-chloro-phenyl)-ethanol in dichloromethane (40 ml). Thereaction mixture was stirred at room temperature for 17 hours undernitrogen, 2N NaOH added (15 ml) and the organic layer was separated,dried (MgSO4), filtered and concentrated to afford the title compoundswhich was used in the next step without further purification. LC/MS:(PS-B3) R_(t) 3.62 [M+H]⁺ 262.91.

33B. 4-[2,2-Bis-(4-chloro-phenyl)-ethyl]-piperazine-1-carboxylic acidtert-butyl ester

To a solution of bis-(4-chloro-phenyl)-acetaldehyde (3.74 mmol) inmethanol under a nitrogen atmosphere, N—BOC-piperazine (1.05 g, 5.61mmol) was added, the reaction mixture was stirred for 1 hour beforeaddition of sodium cyanoborohydride (0.28 g, 4.49 mmol). The reactionmixture was stirred for 18 hours, water added (3 ml) and the solventremoved under reduced pressure. The residue was partitioned betweendichloromethane and water, the organic layer was separated, dried(MgSO4), filtered and concentrated. Purified over flash silicachromatography eluting with ethyl acetate/petroleum ether (3:7) to yieldthe title compound (0.18 g, 11% yield for steps 30A and 30B combined).LC/MS: (PS-A2) R_(t) 2.66 [M-BOC+H]⁺ 335.02.

33C. 1-[2,2-Bis-(4-chloro-phenyl)-ethyl]-piperazine

4-[2,2-Bis-(4-chloro-phenyl)-ethyl]-piperazine-1-carboxylic acidtert-butyl ester was treated with HCl in ethyl acetate (saturated, 5 ml)for 1 hour, solvent removed under reduced pressure to afford the titlecompound as the HCl salt

33D.1-{2-(4-Chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-piperazine

1-[2,2-Bis-(4-chloro-phenyl)-ethyl]-piperazine was reacted with4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole followingthe procedure set out in Example 1 to give the title compound. LC/MS:(PS-B3) R_(t) 2.63 [M+H]⁺ 326.00. ¹H NMR (Me-d₃-OD) δ 3.55-3.68 (8H, m),3.74 (1H, t), 4.10-4.17 (2H, m), 7.39 (2H, d), 7.48 (2H, d), 7.54 (2H,d), 7.70 (2H, d), 8.57 (2H, br s).

Example 341-{2-(4-Chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-piperidine

By following the procedure described in Example 33A, 33B and 33D butsubstituting piperidine for N—BOC-piperazine, the title compound wasobtained. LC/MS: (PS-A2) R_(t) 2.21 [M+H]⁺ 366.09. ¹H NMR (Me-d₃-OD) δ1.44 (2H, m), 1.53 (4H, m), 2.39-2.57 (4H, m), 2.94-3.09 (2H, m), 4.26(1H, t), 7.22-7.35 (6H, m), 7.50 (2H, d), 7.91 (2H, s).

Example 354-{4-[2-Azetidin-1-yl-1-(4-chloro-phenyl)-ethyl]-phenyl}-1H-pyrazole35A. 2-(4-Chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethanol

2,2-Bis-(4-chloro-phenyl)ethanol was reacted with4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole followingthe procedure set out in Example 1 to give the title compound. LC/MS:(PS-A2) R_(t) 2.72 [M+H]⁺ 299.00.

35B. (4-Chloro-phenyl)-[4-(1H-pyrazol-4-yl)-phenyl]-acetaldehyde

By following the procedure described in Example 33A but substituting2,2-Bis-(4-chloro-phenyl)-ethanol for2-(4-Chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]ethanol, the titlecompound was obtained. LC/MS: (PS-B3) R_(t) 2.97 [M+H]⁺ 294.98.

35C.4-{4-[2-Azetidin-1-yl-1-(4-chloro-phenyl)-ethyl]-phenyl}-1H-pyrazole

By following the procedure described in Example 33B but replacingbis-(4-chloro-phenyl)-acetaldehyde and N—BOC-piperazine with(4-Chloro-phenyl)-[4-(1H-pyrazol-4-yl)-phenyl]-acetaldehyde andazetidine, the title compound was obtained. LC/MS: (PS-B3) R_(t) 2.99[M+H]⁺ 338.09. ¹H NMR (Me-d₃-OD) δ 3.57-3.60 (1H, m), 3.63-3.70 (2H, m),3.71-3.77 (1H, m), 4.01 (2H, m), 4.14 (2H, m), 4.40 (1H, t), 7.40 (4H,br s), 7.49 (2H, d), 7.73 (2H, d), 8.69 (2H, br s).

Example 36 1-Phenyl-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethylamine

By following the procedure described in Example 5 but replacing3-bromobenzylmagnesium bromide and3,5-dimethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazolewith 4-bromobenzylmagnesium bromide and4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole, the titlecompound was obtained. LC/MS: (PS-B2) R_(t) 2.44 [M+H]⁺ 264.04. ¹H NMR(Me-d₃-OD) δ 2.99 (2H, d), 4.13 (1H, t), 7.10 (2H, d), 7.20-7.38 (5H,m), 7.45 (2H, d), 7.91 (2H, s).

Example 37[4-(5-Methyl-3-trifluoromethyl-1H-pyrazol-4-yl)-phenyl]-acetonitrile37A.4-Bromo-5-methyl-1-(tetrahydro-pyran-2-yl)-3-trifluoromethyl-1H-pyrazole

To a solution of 4-bromo-5-methyl-3-trifluoromethyl-1H-pyrazole (1.4 g,6.2 mmol, 1.0 equiv) in chloroform (31 ml) was added p-toluene sulphonicacid monohydrate (118 mg, 0.62 mmol, 0.1 equiv). The solution was cooledto 0° C. and 3,4-dihydro-2H-pyran (0.85 ml, 9.3 mmol, 1.5 equiv) wasadded drop-wise over 5 minutes. The mixture was allowed to warm to roomtemperature for 1 hour and the solvents were removed under reducedpressure. The crude mixture was purified by column chromatography(SiO₂), eluting with 0→25% EtOAc-petrol over a linear gradient to affordthe title compound 1.4 g (59%), LCMS (PS-A) R_(t) 3.72 min [M+H]⁺ 314.

37B.{4-[5-Methyl-1-(tetrahydro-pyran-2-yl)-3-trifluoromethyl-1H-pyrazol-4-yl]-phenyl}-acetonitrile

The product of Example 37A,4-bromo-5-methyl-1-(tetrahydro-pyran-2-yl)-3-trifluoromethyl-1H-pyrazole,was reacted with 4-(cyanomethylphenyl)boronic acid (Combi-Blocks, SanDiego, USA Cat. No. 2444-001) under the conditions described in Example1, to give the title compound.

37C.[4-(5-Methyl-3-trifluoromethyl-1H-pyrazol-4-yl)-phenyl]-acetonitrile

To{4-[5-Methyl-1-(tetrahydro-pyran-2-yl)-3-trifluoromethyl-1H-pyrazol-4-yl]-phenyl}-acetonitrile(Example 8B) (35 mg, 0.1 mmol, 1.0 equiv) in ethyl acetate (1 ml) wasadded HCl in ethyl acetate (1 ml) and the mixture was stirred for 1hour. The solvents were removed under reduced pressure and the titlecompound was purified by column chromatography (SiO₂) eluting with alinear gradient (0→30% ethyl acetate-petrol) 16 mg (60%); LCMS (PS-A)R_(t) 2.85 min [M+H]⁺ 266.

37D. Preparation of Compounds of the Formula (I) from[4-(5-Methyl-3-trifluoromethyl-1H-pyrazol-4-yl)-phenyl]-acetonitrile

(i) The product of Example 37B can be reacted with benzaldehyde underthe conditions described in Example 2 to give2-[4-(5-methyl-1-(tetrahydro-pyran-2-yl)-3-trifluoromethyl-1H-pyrazol-4-yl)-phenyl]-3-phenyl-propionitrilewhich can be deprotected by removal of the 1-tetrahydropyranyl groupunder the conditions set out in Example 37C to give2-[4-(5-methyl-3-trifluoromethyl-1H-pyrazol-4-yl)-phenyl]-3-phenyl-propionitrile.

2-[4-(5-Methyl-3-trifluoromethyl-1H-pyrazol-4-yl)-phenyl]-3-phenyl-propionitrileor its 1-tetrahydropyranyl derivative can be reduced according to themethod of Example 6 (and thereafter where necessary deprotectedaccording to the method of Example 41C) to give2-[4-(5-methyl-3-trifluoromethyl-1H-pyrazol-4-yl)-phenyl]-3-phenyl-propylamine.

The product of Example 37B can also be reacted with benzyl magnesiumbromide or phenyl magnesium bromide under the Grignard reactionconditions described in Example 5 to give (following deprotection by themethod of Example 37C)1-benzyl-2-[4-(5-methyl-3-trifluoromethyl-1H-pyrazol-4-yl)-phenyl]-ethylamineand2-[4-(5-methyl-3-trifluoromethyl-1H-pyrazol-4-yl)-phenyl]-1-phenyl-ethylaminerespectively.

Example 38 Construction of Pyrazole Ring System 38A. Synthesis of4-(4-Bromo-phenyl)-3-methyl-1H-pyrazole

To 4-bromophenylacetone (5.0 g, 23.5 mmol, 1.0 equiv) (Acros Organics34216) was added N,N-dimethylformamide dimethyl acetal (11.3 ml, 84.6mmol, 3.6 equiv) and the mixture was heated to 90° C. for 6 hours. Thesolvents were removed and the resulting gum was dissolved in ethanol(235 ml) with additional heating. Hydrazine hydrate (1.37 ml, 28.2 mmol,1.2 equiv) was added and the mixture was heated to reflux for 15 hours.The solvents were removed under reduced pressure and the solid wastriturated with dichloromethane to afford the title compound, 2.24 g(40%); LCMS (PS-A) R_(t) 2.87 min [M+H]⁺ 238. Further material could beisolated from the mother liquor.

38B. Conversion of 4-(4-Bromo-phenyl)-3-methyl-1H-pyrazole to compoundsof the Formula (I)

(i) 4-(4-Bromo-phenyl)-3-methyl-1H-pyrazole can be protected at the1-position of the pyrazole ring by formation of the tetrahydropyranyl(THP) derivative by following the procedure set out in Example 38A. AGrignard reagent can then be prepared from the bromo-phenyl moiety bytreating the protected derivative with magnesium in an ether solvent instandard fashion (see J. March, Advanced Organic Chemistry, 4^(th)Edition, 1992, John Wiley, New York, pages 622-625). The Grignardreagent can be reacted with nitrostyrene (the nitrostyrene having beenprepared by a standard method such as the method described in OrganicSyntheses, Collective Volume 1, page 413) and the resulting nitroethylcompound reduced to give2-{4-[3-methyl-1-(tetrahydro-pyran-2-yl)-1H-pyrazol-4-yl]-phenyl}-2-phenyl-ethylamine.Removal of the tetrahydropyranyl group using the method of Example 8Cgives 2-{4-[3-methyl-1H-pyrazol-4-yl]-phenyl}-2-phenyl-ethylamine.

(ii) The bromo-compound of Example 38A can be converted into compoundsof the formula (I) in which the group A contains a nitrogen atom whichis attached to the group E. The introduction of a nitrogen containingentity can be accomplished by reaction of the compound of Example 38Awith [3-(4-chloro-phenylamino)-propyl]-methyl-carbamic acid tert-butylester under palladium catalysed amination conditions of the typedescribed in Organic Letters, 2002, vol. 4, No. 17, pp 2885-2888,followed by removal of the t-butyloxycarbonyl protecting group bystandard methods.

Example 39 [3-(1H-Pyrazol-4-yl)-phenyl]-acetonitrile

By following the procedure set out in Example 1 but using3-bromophenyl-acetonitrile instead of2-(4-chlorophenyl)-2-phenylethylamine, the title compound was obtained.LCMS (PS-A) 2.35 min [M+H]⁺ 184.

3-(1H-Pyrazol-4-yl)-phenyl]-acetonitrile can be used as an intermediatein the preparation of compounds of the formula (I), for example by meansof an aldehyde condensation reaction as described in Example 2 or aGrignard reaction as described in Example 5.

Example 402-(4-Chloro-phenyl)-N-methyl-2-[4-(1H-pyrazol-4-yl)-phenyl]-acetamide

By following the procedure described in Example 12A followed by 12C butsubstituting 3-(4-Bromo-phenyl)-3-(4-chloro-phenyl)-propionic acid forBis-(4-chloro-phenyl)-acetic acid and ammonia for methyl amine, thetitle compound was obtained. LC/MS (PS-A2): R_(t) 2.64 [M+H]⁺ 326. ¹HNMR (Me-d₃-OD) δ 2.79 (3H, s), 4.94, (1H, br s), 7.26-7.35 (6H, m),7.55-7.57 (2H, m), 7.96 (2H, br s)

Example 41 N-Methyl-2,2-bis-[4-(1H-pyrazol-4-yl)-phenyl]-acetamide

By following the procedure described in Example 40, the title compoundwas obtained. LC/MS (PS-A2): R_(t) 2.19 [M+H]⁺ 358. ¹H NMR (Me-d₃-OD) δ2.80 (3H, s), 4.95, (1H, br s), 7.32 (4H, d), 7.56 (4H, d), 7.98 (4H, brs)

Example 42{2-(4-Chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-methyl-amine42A. 1-(4-Bromo-phenyl)-2-methylamino-ethanol

A solution of 2-(4-bromophenyl)-oxirane (0.5 g, 2.51 mmol) inmethylamine (6.6 ml, 33% by volume in ethanol, 25.12 mmol) was stirredat room temperature under an atmosphere of nitrogen. After 18 hours thesolvent was removed in vacuo and the residue was purified over flashsilica eluting with dichloromethane:methanol:acetic acid:water(120:15:3:2) to afford the desired compound as the acetic acid salt.Further purification over a Phenomenex_Strata_SCX column eluting withmethanol followed by 2N ammonia in methanol gave the desired product.LC/MS: (PS-B3) R_(t) 2.52 [M+H]⁺ 230.

42B. [2-(4-Bromo-phenyl)-2-(4-chloro-phenyl)-ethyl]-methyl-amine

Aluminium chloride (278 mg, 2.087 mmol) was added portionwise to astirred solution of 1-(4-Bromo-phenyl)-2-methylamino-ethanol (160 mg,0.696 mmol) in chlorobenzene (3 ml) and the reaction mixture stirred atroom temperature for 17 hours. Water (2 ml) was added dropwise and thereaction mixture was then partitioned between dichloromethane (100 ml)and saturated NaHCO₃ (30 ml). The organic layer was dried (MgSO₄),filtered and concentrated under reduced pressure. The crude product wasthen purified by Phenomenex_Strata_SCX column chromatography elutingwith methanol followed by 2N ammonia in methanol to afford the desiredproduct. LC/MS: (PS-B3) R_(t) 3.58 [M+H]⁺ 324.

42C.{2-(4-Chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-methyl-amine

A solution of [2-(4-Bromo-phenyl)-2-(4-chloro-phenyl)ethyl]-methyl-amine(6.1 g, 13.716 mmol),4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (5.3 g,27.431 mmol) and K₃PO₄ (10.19 g, 48.00 mmol) in ethanol (7.5 ml),methanol (11.5 ml), toluene (7.5 ml) and water (11.5 ml) was purged withnitrogen for 2 minutes. Bis(tri-t-butylphosphine)palladium (0) (175 mg,2.5 mol %) was then added and the reaction mixture purged with nitrogenfor a further 2 minutes. The mixture was then heated to 80° C., undernitrogen for a period of 17 hours. The solvents were removed and theresidue was partitioned between ethyl acetate and 2N NaOH. The aqueouslayer was extracted with ethyl acetate and the combined organic layerswere washed with brine, dried (MgSO₄) and concentrated under reducedpressure. The crude reaction mixture was purified by columnchromatography (SiO₂), eluting with dichloromethane:methanol:aceticacid:water (90:18:3:2) to afford the title compound (3.6 g); LCMS(PS-A2) R_(t) 2.08 min [M+H]⁺ 312.

Example 43{2-(4-Chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-ethyl-amine

By following the procedures described in Examples 42A through to 42C butsubstituting methylamine for ethylamine, the title compound wasobtained. LC/MS: (PS-A2) R_(t) 2.11 [M+H]⁺ 326. ¹H NMR (Me-d₃-OD) δ 1.15(3H, t), 2.83 (2H, q), 3.35-3.43 (2H, m), 4.25 (1H, t), 7.30-7.48 (6H,m), 7.57 (2H, d), 7.95 (2H, s).

Example 444-{4-[1-(4-Chloro-phenyl)-2-imidazol-1-yl-ethyl]-phenyl}-1H-pyrazole

By following the procedures described in Examples 42A through to 42C butsubstituting methylamine for imidazole, the title compound was obtained.LC/MS: (PS-B3) R_(t) 2.73 [M+H]⁺ 349. ¹H NMR (d₆-DMSO) δ 4.60 (1H, t),4.95 (2H, d), 7.32 (2H, d), 7.42 (4H, s), 7.53-7.60 (3H, m), 7.70 (1H,s), 8.05 (2H, s), 9.0 (1H, s).

Example 45Methyl-{2-(4-phenoxy-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-amine45A. [2-(4-Bromo-phenyl)-2-(4-phenoxy-phenyl)-ethyl]-methyl-amine

By following the procedure described in Example 42B but substitutingchlorobenzene for diphenyl ether and employing nitrobenzene as solvent,the title compound was obtained. LC/MS: (PS-A2) R_(t) 2.54 [M+H]⁺ 382.

45B.Methyl-{2-(4-phenoxy-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-amine

By following the procedure described in Example 42C but substituting[2-(4-Bromo-phenyl)-2-(4-chloro-phenyl)-ethyl]-methyl-amine for[2-(4-Bromo-phenyl)-2-(4-phenoxy-phenyl)-ethyl]-methyl-amine, the titlecompound was obtained. LC/MS: (PS-B3) R_(t) 3.04 [M+H]⁺ 370. ¹H NMR(Me-d₃-OD) δ 2.75 (3H, s), 3.75 (2H, d), 4.38 (1H, t), 6.98 (4H, dd),7.12 (1H, t), 7.33-7.40 (6H, m), 7.61 (2H, d), 7.95 (2H, s).

Example 46{2-(4-Methoxy-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-methyl-amine46A. [2-(4-Bromo-phenyl)-2-(4-methoxy-phenyl)-ethyl]-methyl-amine

By following the procedure described in Example 42B but substitutingchlorobenzene for anisole, the title compound was obtained as a mixtureof regioisomers (ca 4:1) with the corresponding ortho-methoxy analogue.LC/MS: (PS-B3) R_(t) 3.24 [M+H]⁺ 320.

46B. [2-(4-Bromo-phenyl)-2-(4-methoxy-phenyl)-ethyl]-methyl-amine

BOC₂O (941 mg, 4.309 mmol) was added to a solution of[2-(4-Bromo-phenyl)-2-(4-methoxy-phenyl)-ethyl]-methyl-amine (and itsregioisomer) (1.38 g, 4.309 mmol) in dichloromethane (10 ml). Afterstirring at room temperature for 16 hours the solvent was removed underreduced pressure and the crude product was purified by flashchromatography eluting with ethyl acetate/petroleum ether (1:9) to yieldthe intermediate BOC protected compound as the desired single isomer(540 mg). The product was then stirred in a saturated solution of HCl indiethyl ether (30 ml) for 3 days. Removal of the solvent under reducedpressure afforded the title compound as the HCl salt. LC/MS: (PS-B3)R_(t) 3.21 [M+H]⁺ 320.

46C.{2-(4-Methoxy-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-methyl-amine

By following the procedure described in example 42C but substituting[2-(4-Bromo-phenyl)-2-(4-chloro-phenyl)-ethyl]-methyl-amine for[2-(4-Bromo-phenyl)-2-(4-methoxy-phenyl)-ethyl]-methyl-amine, the titlecompound was obtained. LC/MS: (PS-B3) R_(t) 2.52 [M+H]⁺ 308. ¹H NMR(Me-d₃-OD) δ 2.75 (3H, s), 3.75 (2H, dd), 3.80 (3H, s), 4.38 (1H, t),6.95 (2H, d), 7.32 (2H, d), 7.45 (2H, d), 7.70 (2H, d), 8.52 (2H, s).

Example 47Methyl-{2-[4-(pyrazin-2-yloxy)-phenyl]-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-amine47A. 4-[1-(4-Bromo-phenyl)-2-methylamino-ethyl]-phenol

Boron tribromide (7.8 ml, 1.0M in dichloromethane) was added slowly to asolution of [2-(4-Bromo-phenyl)-2-(4-methoxy-phenyl)-ethyl]-methyl-amine(500 mg, 1.56 mmol) in dichloromethane (8 ml) at 0° C., under anatmosphere of nitrogen. The reaction mixture was allowed to warm to roomtemperature and then stirred for a further hour. The mixture was pouredon to ice and then diluted with dichloromethane and saturated NaHCO₃solution. The organic layer was dried (MgSO₄), filtered and concentratedto afford the desired product. LC/MS: (PS-B3) R_(t) 2.76 [M+H]⁺ 306.

47B. [2-(4-Bromo-phenyl)-2-(4-hydroxy-phenyl)-ethyl]-methyl-carbamicacid tert-butyl ester

BOC₂O (269 mg, 1.23 mmol) was added to a solution of4-[1-(4-Bromo-phenyl)-2-methylamino-ethyl]-phenol (360 mg, 1.18 mmol) indichloromethane (20 ml). After stirring at room temperature for 16 hoursthe solvent was removed under reduced pressure and the crude product waspurified by column chromatography (SiO₂), eluting with ethylacetate/petroleum ether (1:4) to yield the title compound. LC/MS: (FL-A)R_(t) 3.85 [M+H]⁺ 406.

47C.{2-(4-Bromo-phenyl)-2-[4-(pyrazin-2-yloxy)-phenyl]-ethyl}-methyl-amine

A solution of[2-(4-Bromo-phenyl)-2-(4-hydroxy-phenyl)-ethyl]-methyl-carbamic acidtert-butyl ester (125 mg, 0.31 mmol), 2-chloropyrazine (35.2 mg, 0.31mmol) and K₂CO₃ (213 mg, 1.54 mmol) in dimethylformamide (8 ml) washeated to 100° C. for 17 hours. Upon cooling, the solvent was removedunder reduced pressure and the residue was partitioned between ethylacetate and saturated NaHCO₃ solution. The organic layer was dried(MgSO₄), filtered and concentrated. The crude product was then treatedwith saturated HCl in diethyl ether (15 ml) and stirred at roomtemperature for 72 hours. The solvent was then removed under reducedpressure and the crude product was purified by Phenomenex_Strata_SCXcolumn chromatography eluting with methanol followed by 2N ammonia inmethanol to afford the desired product (82 mg). LC/MS: (PS-B3) R_(t)3.17 [M+H]⁺ 384.

47D.Methyl-{2-[4-(pyrazin-2-yloxy)-phenyl]-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-amine

By following the procedure described in Example 42C, but substituting[2-(4-Bromo-phenyl)-2-(4-chloro-phenyl)-ethyl]-methyl-amine for{2-(4-Bromo-phenyl)-2-[4-(pyrazin-2-yloxy)-phenyl]-ethyl}-ethyl-amine,the title compound was obtained. LC/MS: (PS-B3) R_(t) 2.48 [M+H]⁺ 372.¹H NMR (Me-d₃-OD) δ 2.80 (3H, s), 3.75-3.90 (2H, m), 4.50 (1H, t), 7.23(2H, d), 7.50 (4H, t), 7.75 (2H, d), 8.12 (1H, d), 8.33 (1H, d), 8.42(2H, s), 8.48 (1H, s).

Example 48 Methyl-{2-phenoxy-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-amine48A. [2-(4-Bromo-phenyl)-2-hydroxy-ethyl]-methyl-carbamic acidtert-butyl ester

BOC₂O (1.90 g, 8.69 mmol) was added to a solution of1-(4-Bromo-phenyl)-2-methylamino-ethanol (2.00 g, 8.69 mmol) indichloromethane (20 ml). After stirring at room temperature for 16 hoursthe solvent was removed under reduced pressure and the crude product waspurified by column chromatography (SiO₂), eluting with ethylacetate/petroleum ether (1:4) to yield the desired product (2.1 g).LC/MS: (PS-B3) R_(t) 3.16 [M+H]⁺ 330.

48B. [2-(4-Bromo-phenyl)-2-phenoxy-ethyl]-methyl-amine

Diethyl azodicarboxylate (358 □l, 2.27 mmol) was added dropwise to asolution of [2-(4-Bromo-phenyl)-2-hydroxy-ethyl]-methyl-carbamic acidtert-butyl ester (500 mg, 1.51 mmol), triphenylphosphine (596 mg, 2.27mmol) and phenol (285 mg, 3.03 mmol) in tetrahydrofuran (10 ml) and thereaction mixture stirred at room temperature, under an atmosphere ofnitrogen, for 17 hours. The solvent was then removed under reducedpressure and the residue was partitioned between ethyl acetate andsaturated NaHCO₃ solution. The organic layer was dried (MgSO₄), filteredand concentrated. The crude product was then purified by columnchromatography (SiO₂), eluting with ethyl acetate/petroleum ether (1:9)to yield the intermediate BOC protected compound, which was then stirredin a saturated solution of HCl in diethyl ether (20 ml) for 24 hours.Removal of the solvent under reduced pressure afforded the titlecompound as the HCl salt. Further purification by Phenomenex_Strata_SCXcolumn chromatography, eluting with methanol followed by 2N ammonia inmethanol, afforded the desired product as the free base (94 mg). LC/MS:(PS-B3) R_(t) 4.04 [M+H]⁺ 406.

48C. Methyl-(2-phenoxy-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl)-amine

By following the procedure described in Example 42C, but substituting[2-(4-Bromo-phenyl)-2-(4-chloro-phenyl)-ethyl]-methyl-amine for[2-(4-Bromo-phenyl)-2-phenoxy-ethyl]-methyl-amine, the title compoundwas obtained. LC/MS: (PS-B3) R_(t) 2.73 [M-PhO+H]⁺ 200. ¹H NMR(Me-d₃-OD) δ 2.50 (3H, s), 2.90 (1H, dd), 3.15 (1H, dd), 5.40 (1H, dd),6.85 (1H, t), 6.90 (2H, d), 7.18 (2H, t), 7.40 (2H, d), 7.55 (2H, d),7.93 (2H, s).

Example 492-{(4-Chloro-phenyl)-[4-(1H-pyrazol-4-yl)-phenyl]-methoxy}-ethylamine49A. (4-Bromo-phenyl)-(4-chloro-phenyl)-methanol

4-Chlorophenylmagnesium bromide (12.97 ml, 1M solution in diethyl ether)was added slowly to a solution of 4-bromobenzaldehyde (2.0 g, 10.81mmol) in tetrahydrofuran (25 ml) at 0° C., under an atmosphere ofnitrogen. The reaction mixture was allowed to warm to room temperatureand was stirred for 17 hours. Water (3 ml) was then added and thesolvent was removed under reduced pressure. The residue was thenpartitioned between ethyl acetate and 1N HCl solution. The organic layerwas washed with brine, dried (MgSO₄), filtered and concentrated. Thecrude product was then purified by column chromatography (SiO₂), elutingwith ethyl acetate/petroleum ether (1:9), to yield the title compound(2.30 g). LC/MS: (PS-B3) R_(t) 3.49 [M−H]⁺ 297.

49B.2-{2-[(4-Bromo-phenyl)-(4-chloro-phenyl)-methoxy]-ethyl}-isoindole-1,3-dione

A mixture of (4-Bromo-phenyl)-(4-chloro-phenyl)-methanol (2.3 g, 7.73mmol), N-(2-hydroxyethyl)phthalimide (1.4 g, 7.36 mmol) andpara-toluenesulfonic acid monohydrate (560 mg, 2.94 mmol) in toluene (50ml) was heated to reflux under Dean-Stark conditions for 17 hours. Uponcooling, the solvent was removed and the residue was partitioned betweenethyl acetate and water. The organic layer was then dried (MgSO₄),filtered and concentrated. The crude product was purified by columnchromatography (SiO₂), eluting with ethyl acetate/petroleum ether (1:4),to yield the title compound (1.95 g). LC/MS: (PS-B3) R_(t) 4.07 noobservable mass ion.

49C.N-(2-{(4-Chloro-phenyl)-[4-(1H-pyrazol-4-yl)-phenyl]-methoxy)-ethyl}-phthalamicacid

By following the procedure described in Example 42C, but substituting[2-(4-Bromo-phenyl)-2-(4-chloro-phenyl)-ethyl]-methyl-amine for2-(2-[(4-Bromo-phenyl)-(4-chloro-phenyl)-methoxy]-ethyl)-isoindole-1,3-dione,the title compound was obtained. LC/MS: (FS-A) R_(t) 2.85 [M−H]⁺ 474.

49D.2-{(4-Chloro-phenyl)-[4-(1H-pyrazol-4-yl)-phenyl]-methoxy}-ethylamine

Hydrazine monohydrate (159 □l, 3.28 mmol) was added to a solution ofN-(2-{(4-Chloro-phenyl)-[4-(1H-pyrazol-4-yl)-phenyl]-methoxy}-ethyl)-phthalamicacid (260 mg, 0.55 mmol) in methanol (6 ml) and the reaction mixturestirred at 80° C. for 16 hours. Upon cooling, the solvent was removedunder reduced pressure and the crude product was purified by columnchromatography (SiO₂), eluting with dichloromethane:methanol:aceticacid:water (90:18:3:2). Further purification by Phenomenex_Strata_SCXcolumn chromatography, eluting with methanol followed by 2N ammonia inmethanol, afforded the desired product as the free base (120 mg). LC/MS:(FL-A) R_(t) 2.07 [M-NH₂CH₂CH₂O+H]⁺ 267. ¹H NMR (Me-d₃-OD) δ 2.85 (2H,t), 3.55 (2H, t), 5.45 (1H, s), 7.35-7.40 (6H, m), 7.58 (2H, d), 7.95(2H, s).

Example 504-{4-[1-(4-Chloro-phenyl)-3-pyrrolidin-1-yl-propyl]-phenyl}-1H-pyrazole

By following the procedure described in Example 8 but substitutingmethylamine for pyrrolidine, the title compound was obtained. LC/MS:(PS-A2) R_(t) 2.25 [M+H]⁺ 366. ¹H NMR (Me-d₃-OD) δ 1.83-1.95 (2H, m),1.95-2.09 (2H, m), 2.4-2.5 (2H, m), 2.88-2.97 (2H, m), 3.02 (2H, dd),3.52-3.61 (2H, m), 4.02 (1H, t), 7.25 (4H, q), 7.32 (2H, d), 7.55 (2H,d), 8.41 (2H, s).

Example 514-{4-[3-Azetidin-1-yl-1-(4-chloro-phenyl)-propyl]-phenyl}-1H-pyrazole

By following the procedure described in Example 8 but substitutingmethylamine for pyrrolidine, the title compound was obtained. LC/MS:(PS-A2) R_(t) 2.18 [M+H]⁺ 352. ¹H NMR (Me-d₃-OD) δ 2.12-2.25 (2H, m),3.00 (2H, t), 3.85-3.98 (5H, m), 4.05-4.17 (2H, m), 7.18 (2H, d), 7.19(4H, s), 7.45 (2H, d), 7.83 (2H, s).

Example 52Methyl-{3-naphthalen-2-yl-3-[4-(1H-pyrazol-4-yl)-phenyl]-propyl}-amine

By following the procedure described in Example 8 but substituting4-chlorophenylmagnesium bromide for 2-naphthylmagnesium bromide, thetitle compound was obtained. LC/MS: (PS-A2) R_(t) 2.26 [M+H]⁺ 342. ¹HNMR (Me-d₃-OD) δ 2.57-2.70 (2H, m), 2.70 (3H, s), 2.90-3.10 (2H, m),4.32 (1H, t), 7.40-7.52 (5H, m), 7.70 (2H, m), 7.80-7.90 (4H, m), 8.70(2H, s).

Example 53Dimethyl-(4-{3-methylamino-1-[4-(1H-pyrazol-4-yl)-phenyl]-propyl}-phenyl)-amine

By following the procedure described in Example 8 but substituting4-chlorophenylmagnesium bromide for 4-(N,N-dimethyl)anilinemagnesiumbromide, the title compound was obtained. LC/MS: (PS-A2) R_(t) 1.55[M+H]⁺ 335. ¹H NMR (Me-d₃-OD) δ, 2.46-2.60 (2H, m), 2.69 (3H, s), 2.95(2H, t), 3.27 (6H, s), 4.25 (1H, t), 7.45 (2H, d), 7.60-7.72 (6H, m),8.50 (2H, s).

Example 54{3-(4-Fluoro-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propyl}-methyl-amine

By following the procedure described in Example 8 but substituting4-chlorophenylmagnesium bromide for 4-fluorophenylmagnesium bromide, thetitle compound was obtained. LC/MS: (PS-A2) R_(t) 2.05 [M+H]⁺ 310. ¹HNMR (Me-d₃-OD) δ 2.40-2.55 (2H, d), 2.70 (3H, s), 2.90-3.0 (2H, m), 4.12(1H, t), 7.05 (2H, t), 7.32-7.40 (4H, m), 7.63 (2H, d), 8.33 (2H, s).

Example 554-{4-[4-(4-Chloro-phenyl)-piperidin-4-yl]-phenyl}-1H-pyrazole-3-carbonitrile

Following the procedure of Example 1 but using4-(4-Chloro-phenyl)-4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-piperidineinstead of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazoleand 4-bromo-1H-pyrazole-3-carbonitrile instead of2-(4-chlorophenyl)-2-phenylethylamine hydrochloride gave the titlecompound. LC/MS: (PS-A2) R_(t) 2.22 [M+H]⁺ 363. ¹H NMR (Me-d₃-OD) δ2.52-2.70 (4H, m), 3.10-3.20 (4H, m), 7.25 (4H, s), 7.37 (2H, d), 7.58(2H, d), 8.02 (1H, s).

Example 563-(4-Phenoxy-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propylamine

By following the procedure described in Example 8 but substituting4-chlorophenylmagnesium bromide for 4-phenoxyphenylmagnesium bromide andmethylamine for ammonia the title compound was obtained. LC/MS: (PS-A2)R_(t) 2.28 [M+H]⁺ 370.34. ¹H NMR (Me-d₃-OD) δ 2.38-2.46 (2H, m),2.85-2.92 (2H, t), 4.03-4.10 (1H, t), 6.94-7.0 (4H, d), 7.08-7.14 (1H,t), 7.30-7.39 (6H, m), 7.55-7.58 (2H, d), 7.90-7.97 (2H, br s),8.54-8.60 (1H, br s).

Example 571-{(4-Chloro-phenyl)-[4-(1H-pyrazol-4-yl)-phenyl]-methyl}-piperazine

By following the procedure described in Example 1 but substituting2-(4-chlorophenyl)-2-phenylethylamine hydrochloride for1-(4,4′-dichloro-benzhydryl)-piperazine gave the title compound. LC/MS:(PS-B3) R_(t) 2.82 [M−H]⁺ 351.27. ¹H NMR (Me-d₃-OD) δ 3.0-3.25 (4H, m),3.45-3.65 (4H, m), 5.05-5.25 (1H, br s), 7.40-7.50 (2H, d), 7.65-7.83(6H, m), 8.45 (2H, s).

Example 581-Methyl-4-{phenyl-[4-(1H-pyrazol-4-yl)-phenyl]-methyl}-[1,4]diazepane

By following the procedure described in Example 1 but substituting2-(4-chlorophenyl)-2-phenylethylamine hydrochloride for1-[p-chlorodiphenylmethyl]-4-methyl-1,4-diazacycloheptanedihydrochloride gave the title compound. LC/MS: (PS-B3) R_(t) 2.85[M+H]⁺ 347.18. ¹H NMR (Me-d₃-OD) δ 2.25-2.60 (2H, br m), 3.00 (3H, s),3.40-4.18 (8H, br m), 5.78 (1H, s), 7.40-7.48 (1H, m), 7.49-7.55 (2H,t), 7.75-7.80 (2H, d), 7.82-7.98 (4H, m), 8.32 (2H, s).

Example 59{3-(3-Chloro-phenoxy)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propyl}-methyl-amine59A. 1-(4-Bromo-phenyl)-3-chloro-propan-1-ol

(J. Med. Chem, 2004, 47, 3924-3926)

To a solution of 1-(4-Bromo-phenyl)-3-chloro-propan-1-one (1 g, 4.04mmol) in tetrahydrofuran (9 ml) and water (0.58 ml) was added sodiumborohydride (0.16 g, 4.28 mmol). The reaction mixture was stirred atroom temperature for 2 hours, quenched with careful addition of waterand extracted with ethyl acetate. The organic layers were separated,dried (MgSO₄), filtered and concentrated to afford the title compound,which was used in the next step without further purification. LC/MS:(PS-A2) R_(t) 3.07 [M+H]⁺ No ionization.

59B. [3-(4-Bromo-phenyl)-3-(3-chloro-phenoxy)-propyl]-chloride

3-Chlorophenol was reacted with 1-(4-Bromo-phenyl)-3-chloro-propan-1-olfollowing the procedure set out in Example 48B to give the titlecompound, which was used in the next step without further purification.

59C. [3-(4-Bromo-phenyl)-3-(3-chloro-phenoxy)-propyl]-methyl-amine

A solution of 3-(4-Bromo-phenyl)-3-(3-chloro-phenoxy)-propyl]-chloridein 33% methylamine in ethanol (4 ml) was heated in a CEM microwave at100° C. for 30 minutes using 50 W power. Solvent was removed and thecrude product was purified over Phenomenex_Strata_SCX ion exchangecolumn eluting with methanol followed by 2N ammonia in methanol. Theproduct was purified by column chromatography (SiO₂), eluting withdichloromethane to dichloromethane:methanol:acetic acid:water(90:18:3:2) using the SP4 biotage to afford the title compound. LC/MS:(PS-B3) R_(t) 3.42 [M+H]⁺ 356.19.

59D.{3-(3-Chloro-phenoxy)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propyl}-methyl-amine

[3-(4-Bromo-phenyl)-3-(3-chloro-phenoxy)-propyl]-methyl-amine wasreacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolefollowing the procedure set out in Example 1 to give the title compound.LC/MS: (PS-B3) R_(t) 2.80 [M+H]⁺ 342.26. ¹H NMR (Me-d₃-OD) δ 2.19-2.30(1H, m), 2.30-2.45 (1H, m), 2.72 (3H, s), 3.10-3.28 (2H, m), 5.40-5.47(1H, m), 6.80-6.88 (1H, d), 6.88-6.94 (1H, d), 6.96 (1H, s), 7.15-7.20(1H, t), 7.38-7.45 (2H, d), 7.57-7.65 (2H, d), 7.98 (2H, s).

Example 60Methyl-{2-phenyl-2-[6-(1H-pyrazol-4-yl)-pyridin-3-yl]-ethyl}-amine 60A.6-(3-Methyl-1-trityl-1H-pyrazol-4-yl)-nicotinonitrile

To a solution of 6-Chloro-nicotinonitrile (0.2 g, 1.49 mmol) and3-methyl-1-trityl-1H-pyrazole-4-boronic acid* (0.5 g, 1.36 mmol) inethylene glycol dimethyl ether (3 ml), was added sodium carbonate (0.36g, 3.39 mmol) in water (1.5 ml). The reaction mixture was degassed withnitrogen before addition of tetrakis(triphenylphosphine)palladium (0)and then heated in a CEM microwave at 135° C. for 30 minutes (50 Wpower). Reaction partitioned between water and ethyl acetate, aqueousbasified with 2N NaOH, organic extracts were combined, dried (MgSO₄) andsolvent removed. Crude product suspended in small volume of methanol,white precipitate filtered to afford the title compound (0.32 g, 53%yield). LC/MS: (PS-A2) R_(t) 4.52 [M+H]⁺ 427.26.

* This starting material can be made by the method described inEP1382603A1

60B.(4-Chloro-phenyl)-[6-(3-methyl-1-trityl-1H-pyrazol-4-yl)-pyridin-3-yl]-methanone

To a solution of 6-(3-Methyl-1-trityl-1H-pyrazol-4-yl)-nicotinonitrile(0.5 g, 1.17 mmol) in dry tetrahydrofuran (4 ml) was added4-chlorobenzenemagnesium bromide (1.52 ml, 1.52 mmol, 1M in diethylether); the reaction mixture was stirred under nitrogen for 16 hours.The reaction was quenched to below pH 2 by the addition of 2N HCl andstirred for 1 hour. Then adjusted to pH 8 with saturated sodiumbicarbonate and extracted with ethyl acetate. Organic extracts werecombined, dried (MgSO₄), solvent removed and residue purified by columnchromatography (SiO₂), eluting with petrol to ethyl acetate:petroleumether (15:85) to yield the title compound (0.49 mg, 77% yield). LC/MS:(PS-A2) R_(t) 4.45 [M+H]⁺ 540.30, 542.28.

60C.{2-(4-Chloro-phenyl)-2-[6-(3-methyl-1-trityl-1H-pyrazol-4-yl)-pyridin-3-yl]-vinyl}-methyl-(1-phenyl-ethyl)-amine

n-Butyllithium (0.47 ml, 0.76 mmol, 1.6M in Hexanes) was added dropwiseto a solution of(R)(Diphenyl-phosphinoylmethyl)-methyl-(1-phenyl-ethyl)-amine* (0.18 g,0.51 mmol) in dry tetrahydrofuran (9 ml) at −15° C. After 15 minutes asolution of(4-Chloro-phenyl)-[6-(3-methyl-1-trityl-1H-pyrazol-4-yl)-pyridin-3-yl]-methanone(0.14 g, 0.25 mmol) in tetrahydrofuran (0.9 ml) was added and thereaction mixture was stirred for a further 30 minutes at −15° C. beforewarming to room temperature over 1 hour. The reaction mixture wasquenched with water, extracted with diethyl ether, organic extracts werecombined, dried (MgSO₄) and concentrated to afford the title compound,which was used in the next step without further purification.

* This starting material can be made by the method described inTetrahedron Asymmetry, 2003, 14, 1309-1316.

60D. Methyl-{2-phenyl-2-[6-(1H-pyrazol-4-yl)-pyridin-3-yl]-ethyl}-amine

To a solution of{2-(4-Chloro-phenyl)-2-[6-(3-methyl-1-trityl-1H-pyrazol-4-yl)-pyridin-3-yl]-vinyl}-methyl-(1-phenyl-ethyl)-aminein ethanol was added palladium, 10 wt. % on activated carbon and thereaction mixture was subjected to a hydrogen atmosphere for 17 hours.The mixture was filtered through Celite®, the mother liquor wasconcentrated, the residue was purified by column chromatography (SiO₂),eluting with dichloromethane:methanol:acetic acid:water (240:20:3:2) todichloromethane:methanol:acetic acid:water (90:18:3:2) to afford thetitle compound. LC/MS: (PS-A2) R_(t) 1.59 [M+H]⁺ 293.18. ¹H NMR(Me-d₃-OD) δ 2.35 (3H, s), 2.40 (3H, s), 3.25 (2H, s), 4.15-4.20 (1H,t), 7.10-7.18 (1H, m), 7.25 (4H, m), 7.45 (1H, d), 7.67 (1H, dd), 7.80(1H, s), 8.38 (1H, s).

Example 614-{4-[1-(4-Chloro-phenyl)-3-imidazol-1-yl-propyl]-phenyl}-1H-pyrazole61A. 1-(4-Bromo-phenyl)-3-imidazol-1-yl-propan-1-ol

A solution of 1-(4-Bromo-phenyl)-3-chloro-propan-1-ol* (1.5 g, 6.01mmol) and imidazole (1.23 g, 18.03 mmol) in dimethylformamide (18 ml)was heated at 100° C. for 18 hrs then partitioned between water andethyl acetate. The organic extracts were combined, dried (MgSO₄),filtered, concentrated and purified by column chromatography (SiO₂),eluting with methanol:dichloromethane (2:98) to methanol:dichloromethane(6:94) to afford the title compound (0.75 g, 44% yield). LC/MS: (PS-B3)R_(t) 2.48 [M+H]⁺ 281.14, 283.11.

*This starting material can be made by the method described in Example43A.

61B. 1-[3-(4-Bromo-phenyl)-3-(4-chloro-phenyl)-propyl]-1H-imidazole

Chlorobenzene (5 ml) was reacted with1-(4-Bromo-phenyl)-3-imidazol-1-yl-propan-1-ol (0.41 mg, 1.46 mmol)following the procedure set out in Example 42B to give the titlecompound (0.37 g, 67% yield). LC/MS: (PS-A2) R_(t) 2.40 [M+H]⁺ 375.16,377.17.

61C.4-{4-[1-(4-Chloro-phenyl)-3-imidazol-1-yl-propyl]-phenyl}-1H-pyrazole

1-[3-(4-Bromo-phenyl)-3-(4-chloro-phenyl)-propyl]-1H-imidazole wasreacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolefollowing the procedure set out in Example 1 to give the title compound.LC/MS: (PS-A2) R_(t) 2.21 [M+H]⁺ 363.28. ¹H NMR (Me-d₃-OD) δ 2.55-2.70(2H, m), 3.85-3.95 (1H, m), 3.95-4.10 (2H, m), 7.05 (1H, s), 7.10-7.60(9H, m), 7.65 (1H, s), 7.90-8.00 (2H, d).

Example 62 4-[4-(3-Imidazol-1-yl-1-phenoxy-propyl)-phenyl]-1H-pyrazole62A. 1-[3-(4-Bromo-phenyl)-3-phenoxy-propyl]-1H-imidazole

Phenol was reacted with 1-(4-Bromo-phenyl)-3-imidazol-1-yl-propan-1-ol*following the procedure set out in Example 48B to give the titlecompound. LC/MS: (PS-A2) R_(t) 2.30 [M+H]⁺ 357.26, 359.27.

*This starting material can be made by the method described in Example47A.

62B. 4-[4-(3-Imidazol-1-yl-1-phenoxy-propyl)-phenyl]-1H-pyrazole

1-[3-(4-Bromo-phenyl)-3-phenoxy-propyl]-1H-imidazole was reacted with4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole followingthe procedure set out in Example 1 to give the title compound. LC/MS:(PS-A2) R_(t) 2.05 [M+H]⁺ 345.30. ¹H NMR (Me-d₃-OD) δ 2.30-2.55 (2H, m),4.25-4.45 (2H, m), 5.10-5.15 (1H, m), 6.80-6.90 (3H, m), 7.10 (1H, s),7.15-7.20 (2H, t), 7.25 (1H, s), 7.35-7.40 (2H, d), 7.55-7.60 (2H, d),7.85 (1H, s), 7.95 (2H, s).

Example 63 4-{4-[4-(1H-Pyrazol-4-yl)-phenyl]-piperidin-4-yl}-phenol

By following the procedure described in Example 14 but substitutingchlorobenzene for phenol using nitrobenzene as the solvent, the titlecompound was obtained. LC/MS: (PS-A3) R_(t) 5.07 [M+H]⁺ 320. ¹H NMR(d₆-DMSO) δ 7.97 (2H, s), 7.49 (2H, d), 7.25 (2H, d), 7.10 (2H, d), 6.68(2H, d), 2.840 (4H, bs), 2.376 (4H, bs).

Example 641-{(4-Chloro-phenyl)-[4-(1H-pyrazol-4-yl)-phenyl]-methyl}-piperazine

By following the procedure described in Example 57, the title compoundwas obtained. LCMS: (PS-A3) R_(t) 6.38 [M+H]⁺ 319. ¹H NMR (Me-d₃-OD) δ8.53 (2H, s), 7.90 (2H, d), 7.83 (2H, d), 7.71 (2H, d), 7.40-7.30 (3H,m), 5.70 (1H, s), 3.68 (4H, bs), 3.51-3.48 (4H, m).

Example 65{2-(4-Fluoro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-methyl-amine65A. [2-(4-Bromo-phenyl)-2-(4-fluoro-phenyl)-ethyl]-carbamic acid benzylester

To a solution of 3-(4-fluorophenyl)-3-(4-bromophenyl)propionic acid*(1.0 g, 3.09 mmol) in acetone (4 ml) at 0° C. was sequentially addedtriethylamine (561 ul, 4.02 mmol) in acetone (1.6 ml) and ethylchloroformate (443 ul, 4.64 mmol) in acetone (1.6 ml). The reaction wasallowed to warm to room temperature, stirred for 30 minutes beforecooling again to 0° C. and sodium azide (402 mg, 6.18 mmol) in water(1.6 ml) was added. The resultant brown solution was stirred for 45minutes before addition of water (10 ml) and diethyl ether (10 ml). Theaqueous layer was separated and extracted further with ethyl acetate (10ml). The combined organic liquors were washed with saturated brine,dried (MgSO₄) and concentrating in vacuo. The residue was dissolved inanhydrous toluene (12 ml) before addition of benzyl alcohol (567 ul,9.27 mmol) and heating to 80° C. for 40 minutes. The reaction wasallowed to cool to room temperature before addition of ethyl acetate (50ml) and saturated sodium bicarbonate (50 ml). The organic liquors wereseparated and washed with further bicarbonate solution (50 ml),hydrochloric acid (2N, 100 ml) and saturated brine (50 ml) before drying(MgSO₄) and concentrating in vacuo. The residue was purified by columnchromatography (SiO₂), eluting with ethyl acetate/petrol (5:95) gradientto (15:85) to afford the title compound (594 mg, 45%). LC/MS: (PS-A2)R_(t) 3.18 No ionisation.

* This starting material can be made by the method described in Example8A to 8C, substituting 4-chlorophenylmagneslum bromide for4-fluorophenylmagnesium bromide

65B. {2-(4-Fluoro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-carbamicacid benzyl ester

[2-(4-Bromo-phenyl)-2-(4-fluoro-phenyl)-ethyl]-carbamic acid benzylester was reacted with4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole followingthe procedure set out in Example 1 to give the title compound. LC/MS:(PS-A2) R_(t) 3.20 [M+H]⁺ 416.

65C.{2-(4-Fluoro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-methyl-amine

Lithium aluminium hydride (5.3 ml, 5.30 mmol, 1M in tetrahydrofuran) wasslowly added to{2-(4-Fluoro-phenyl)-2-[4-(1-pyrazol-4-yl)-phenyl]-ethyl}-carbamic acidbenzyl ester (439 mg, 1.06 mmol) in tetrahydrofuran (5 ml) at 0° C.under nitrogen. The reaction mixture was allowed to warm to roomtemperature, stirred for 51 hours and quenched with water (5 ml),aqueous sodium hydroxide (2N, 5 ml) and ethyl acetate (10 ml). Theaqueous layer was separated, extracted with ethyl acetate (2×20 ml). Thecombined organic liquors were washed with saturated aqueous brine thendried (MgSO₄) and concentrated in vacuo. The residue was purified bycolumn chromatography (SiO₂), eluting withdichloromethane:methanol:acetic acid:water (120:15:3:2) gradient to(90:18:3:2) to afford the title compound, which was subsequentlyconverted to the hydrochloride salt (100 mg, 32%). LC/MS: (PS-A2) R_(t)1.87 [M+H]⁺ 296. ¹H NMR (Me-d₃-OD) δ 8.20 (2H, s), 7.57 (2H, d),7.34-7.29 (4H, m), 7.02 (2H, t), 4.32 (1H, t), 3.67 (2H, d), 2.65 (3H,s).

Example 66{2-(3-Chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-methyl-amine

By following the procedure described in Example 65 but substituting4-fluorophenylmagnesium bromide for 3-chlorophenylmagnesium bromide thetitle compound was obtained. LC/MS: (PS-A3) R_(t) 4.92 [M+H]⁺ 312. ¹HNMR (Me-d₃-OD) δ 8.50 (2H, s), 7.63 (2H, d), 7.39 (2H, d), 7.34 (1H, s),7.30-7.20 (3H, m), 4.40 (1H, t), 3.70 (2H, d), 2.65 (3H, s).

Example 674-[4-(2-Methoxy-ethoxy)-phenyl]-4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidine67A. 4-(4-Bromo-phenyl)-4-(4-hydroxy-phenyl)-piperidine-1-carboxylicacid tert-butyl ester

By following the procedure described in Example 47B but substituting4-[1-(4-Bromo-phenyl)-2-methylamino-ethyl]-phenol for4-[4-(4-Bromo-phenyl)-piperidin-4-yl]-phenol* the title compound wasobtained. ¹H NMR (d₆-DMSO) δ 7.45 (2H, d), 7.25 (2H, d), 7.11 (2H, d),6.68 (2H, d), 3.35-3.18 (4H, m), 2.31-2.20 (4H, m), 1.38 (9H, s).

* This starting material can be made by the method described in Example63

67B.4-(4-Bromo-phenyl)-4-[4-(2-methoxy-ethoxy)-phenyl]-piperidine-1-carboxylicacid tert-butyl ester

A solution of4-(4-Bromo-phenyl)-4-(4-hydroxy-phenyl)piperidine-1-carboxylic acidtert-butyl ester (100 mg, 0.23 mmol), 2-bromoethyl methylether (200 ul)and potassium carbonate (64 mg, 0.46 mmol) in dimethylformamide (2 ml)was heated in a CEM Explorer™ microwave to 50° C. for 30 minutes using50 watts power. The reaction was poured into sodium hydroxide (2N, 4ml), stirred for 5 minutes then extracted into ethyl acetate (2×30 ml).The combined organic liquors were dried (MgSO₄), concentrated and theresidue was purified by column chromatography (SiO₂), eluting with ethylacetate/petrol (25:75) gradient to (50:50) to afford the title compound(82 mg). LCMS: (PS-A2) R_(t) 4.00 [M+H]⁺ 490.

67C.4-[4-(2-Methoxy-ethoxy)-phenyl]-4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidine

4-(4-Bromo-phenyl)-4-[4-(2-methoxy-ethoxy)-phenyl]-piperidine-1-carboxylicacid tert-butyl ester was reacted with4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)1H-pyrazole following theprocedure set out in Example 1, substituting tetrakis triphenylphosphinepalladium (0) as catalyst, the title compound was obtained. LC/MS:(PS-A2) R_(t) 3.27 [M+H]⁺ 478.

67D.4-[4-(2-Methoxy-ethoxy)-phenyl]-4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidine

Trifluoroacetic acid (1 ml) was added to a solution of4-[4-(2-Methoxy-ethoxy)phenyl]-4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidine(87 mg) in dichloromethane (1 ml). After 30 minutes at room temperature,the reaction was concentrated. The residue was dissolved in ethylacetate then extracted into hydrochloric acid (2N, 2×20 ml). Thecombined aqueous fractions were washed with ethyl acetate then basified(2N NaOH) before back-extraction into ethyl acetate (2×20 ml). Thecombined organic liquors were washed with saturated brine solution thendried (MgSO₄) and concentrated to yield the title compound (66 mg).LCMS: (PS-A3) R_(t) 6.08 [M+H]⁺ 378. ¹H NMR (Me-d₃-OD) δ 7.92 (2H, s),7.51 (2H, d), 7.31 (2H, d), 7.25 (2H, d), 6.89 (2H, d), 4.13 (2H, t),3.73 (2H, t), 3.42 (3H, s), 2.94 (4H, bs), 2.44 (4H, bs).

Example 684-[4-(3-Methoxy-propoxy)-phenyl]-4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidine68A.4-(4-Bromo-phenyl)-4-[4-(3-methoxy-propoxy)-phenyl]-piperidine-1-carboxylicacid tert-butyl ester

Tosyl chloride (572 mg, 3.0 mmol) was added to a solution of3-methoxypropanol (191 ul, 2.0 mmol) in pyridine (1 ml). This wasstirred at room temperature for 5.5 hours then diluted with ethylacetate (20 ml) and washed with hydrochloric acid (2N, 3×10 ml) andsaturated brine (10 ml). The liquors were dried (MgSO₄) and concentratedto furnish a colourless oil (600 mg). This oil was dissolved indimethylformamide (2 ml) and to this solution was added potassiumcarbonate (64 mg, 0.46 mmol) and4-(4-Bromo-phenyl)-4-(4-hydroxy-phenyl)-piperidine-1-carboxylic acidtert-butyl ester* (100 mg, 0.231 mmol). The resultant mixture wasstirred at 100° C. for 4 hours. Once cooled, water (20 ml) was added andthe mixture was extracted with ethyl acetate (3×10 ml). The combinedorganic liquors were washed with brine (10 ml) before drying (MgSO₄) andconcentrating. The residue was purified by column chromatography (SiO₂),eluting with a gradient from 10-20% ethyl acetate/petrol to furnish thetitle compound as a colourless oil (131 mg). LCMS: R_(t) 4.20 [M+H]⁺504.

* This starting material can be made by the method described in Example67A

68B.4-[4-(3-Methoxy-propoxy)-phenyl]-4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidine

By following the procedure described in Example 67C and 67D butsubstituting4-(4-Bromo-phenyl)-4-[4-(2-methoxy-ethoxy)-phenyl]-piperidine-1-carboxylicacid tert-butyl ester for4-(4-Bromo-phenyl)-4-[4-(3-methoxy-propoxy)-phenyl]-piperidine-1-carboxylicacid tert-butyl ester the title compound was obtained. LCMS: R_(t) 6.65[M+H]⁺ 392. ¹H NMR (Me-d₃-OD) δ 7.94 (2H, s), 7.57 (2H, d), 7.34 (2H,d), 7.27 (2H, d), 6.91 (2H, d), 4.04 (2H, t), 3.56 (2H, t), 3.34-3.33(5H, m), 3.24-3.22 (4H, m), 2.67-2.66 (4H, m)

Example 693-(3,4-Dichloro-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propionamide

By following the procedure described in Example 9A and 9B butsubstituting 3,4-difluorophenylmagnesium bromide for3,4-dichlorophenylmagnesium bromide, the title compound was obtained.LC/MS: (PS-A3) R_(t) 9.82 [M+H]⁺ 360.14, 362.12. ¹H NMR (Me-d₃-OD) δ2.90-3.00 (2H, d), 4.50-4.60 (1H, t), 7.10-7.30 (3H, m), 7.40-7.45 (2H,d), 7.50-7.55 (2H, d), 7.85-8.05 (2H, br s).

Example 702-(4-{2-Methylamino-1-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-phenoxy)-isonicotinamide

By following the procedure described in Example 47, but substituting2-chloropyrazine for 2-chloro-4-cyanopyridine, the title compound wasobtained. LC/MS: (PS-B3) R_(t) 2.27 [M+H]⁺ 414. ¹H NMR (Me-d₃-OD) δ 2.45(3H, s), 3.55 (1H, dd), 3.65 (1H, dd), 4.25 (1H, t), 7.10 (2H, d),7.30-7.38 (3H, m), 7.40 (2H, d), 7.48 (1H, d), 7.56 (2H, d), 7.95 (2H,s), 8.22 (1H, d).

Example 71{2-(4-Chloro-phenoxy)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-methyl-amine

By following the procedure described in Example 48, but substitutingphenol for 4-chlorophenol, the title compound was obtained. LC/MS:(PS-A3) R_(t) 2.29 [M-ClPhO+H]⁺ 200. ¹H NMR (Me-d₃-OD) δ 2.50 (3H, s),2.86 (1H, dd), 3.10 (1H, dd), 5.35 (1H, dd), 6.89 (2H, d), 7.17 (2H, d),7.40 (2H, d), 7.57 (2H, d), 7.93 (2H, s).

Example 723-{2-(4-Chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-amino)-propan-1-ol

By following the procedure described in Example 20 but substitutingdimethylamine for 3-aminopropan-1-ol the title compound was obtained.LC/MS: (PS-A2) R_(t) 2.05 [M+H]⁺ 356. ¹H NMR (Me-d₃-OD) δ 1.87 (2H,quintet), 1.98 (AcOH, s), 3.23 (2H, t), 3.68 (2H, t), 3.75 (2H, dd), 4.4(1H, t), 7.36 (2H, d), 7.4 (4H, s), 7.62 (2H, d), 7.97 (2H, s).

Example 732-{2-(4-Chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethylamino}-ethanol

By following the procedure described in Example 20 but substitutingdimethylamine for 2-aminoethan-1-ol the title compound was obtained.LC/MS: (PS-A2) R_(t) 2.05 [M+H]⁺ 342. ¹H NMR (Me-d₃-OD) δ 1.98 (AcOH,s), 3.10 (2H, s), 3.69 (2H, dd), 3.78, (2H, t), 4.39 (1H, t), 7.36 (2H,d), 7.38 (4H, s), 7.61 (2H, d), 7.97 (2H, s).

Example 74{2-(4-Chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-cyclopropylmethyl-amine

By following the procedure described in Example 20 but substitutingdimethylamine for cyclopropylmethylamine the title compound wasobtained. LC/MS: (PS-A2) R_(t) 2.21 [M+H]⁺ 352. ¹H NMR (Me-d₃-OD) δ−0.4-0.3 (2H, m), 0.35-0.40 (2H, m), 0.78-0.87 (1H, m), 2.42 (2H, d),3.15-3.25 (2H, m), 4.11 (1H, t), 7.16-7.27 (6H, m), 7.45 (2H, d), 7.82,(2H, s).

Example 75Methyl-[2-[4-(1H-pyrazol-4-yl)-phenyl]-2-(4-pyridin-3-yl-phenyl)-ethyl]-amine

By following the procedure described in Example 1 but substituting4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole for3-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine and couplingto{2-(4-Chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-methyl-amine*,the title compound was obtained. LC/MS: (PS-B3) R_(t) 2.42 [M+H]⁺ 355.¹H NMR (Me-d₃-OD) δ 1.94 (AcOH, s), 2.72 (3H, s), 3.73 (2H, d), 4.46(1H, t), 7.41 (2H, d), 7.51-7.56 (3H, m), 7.63 (2H, d), 7.70 (2H, d),7.96 (2H, s), 8.10 (1H, dt), 8.53 (1H, dd), 8.80 (1H, d).

* This starting material can be made by the method described in Example21.

Example 764-{3-Methylamino-1-[4-(1H-pyrazol-4-yl)-phenyl]-propyl}-phenol

By following the procedure described in Example 8 but substituting4-chlorophenylmagnesium bromide for 4-anisylmagnesium bromide, the titlecompound can be obtained LC/MS: (PS-A2) R_(t) 1.82 [M+H]⁺ 308. ¹H NMR(Me-d₃-OD) δ 1.92 (AcOH, s), 2.34-2.43 (2H, m), 2.64 (3H, s), 2.86-2.92(2H, m), 3.96 (1H, t), 6.75 (2H, d), 7.13 (2H, d), 7.29 (2H, d), 7.52(2H, d), 7.93 (2H, d).

Example 773-(4-Methoxy-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propylamine

By following the procedure described in Example 8 but substituting4-chlorophenylmagnesium bromide for 4-anisylmagnesium bromide andmethylamine for ammonia (2M in methanol), the title compound wasobtained. LC/MS: (PS-A2) R_(t) 1.82 [M+H]⁺ 308. ¹H NMR (Me-d₃-OD) δ2.23-2.32 (2H, m), 2.74 (2H, dd), 3.65 (3H, s), 3.89 (1H, t), 6.77 (2H,d), 7.11 (2H, s), 7.17 (2H, d), 7.41 (2H, d), 7.71 (2H, s), 8.41 (HCO₂H,br s).

Example 784-(4-Chloro-phenyl)-4-[4-(3-methyl-1H-pyrazol-4-yl)-phenyl]-piperidine78A.4-(4-Chloro-phenyl)-4-[4-(3-methyl-1-trityl-1H-pyrazol-4-yl)-phenyl]-pideridine

4-(4-bromo-phenyl)-4-(4-chloro-phenyl)-piperidine hydrochloride wasreacted with 3-methyl-1-trityl-1H-pyrazole-4-boronic acid* following theprocedure set out in Example 1, but usingtetrakis(triphenylphosphine)palladium (0) as the catalyst to give thetitle compound. LC/MS: (PS-B3) R_(t) 2.78 min [M+H]⁺ 594.

* This starting material can be made by the method described inEP1382603

78B.4-(4-Chloro-phenyl)-4-[4-(3-methyl-1H-pyrazol-4-yl)-phenyl]-piperidine

A suspension of4-(4-chloro-phenyl)-4-[4-(3-methyl-1-trityl-1H-pyrazol-4-yl)-phenyl]-piperidine(178 mg, 0.30 mmol) in 5N hydrochloric acid (5 mL), THF (5 mL) andmethanol (5 mL) was stirred for 140 minutes. The organic solvents wereremoved in vacuo then the resulting solution was diluted with 2N HCl andwashed with ether. The aqueous phase was basified by addition of sodiumhydroxide pellets then extracted with ethyl acetate. This organicextract was washed with brine, dried (MgSO₄), filtered and concentratedto give a residue which was purified by column chromatography (SiO₂),eluting with a gradient of 2M ammonia in methanol (5% to 7.5%) anddichloromethane. The product was further purified by preparative HPLC togive the title compound which was converted to its dihydrochloride salt(84 mg, 80%); LCMS (PS-A3) R_(t) 6.86 min [M+H]⁺ 352. ¹H NMR (Me-d₃-OD)δ 2.55 (3H, s), 2.70-2.75 (4H, m), 3.22-3.27 (4H, m), 7.35-7.41 (4H, m),7.47-7.54 (4H, m), 8.32 (2H, s).

Example 79 2-(4-Chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-morpholine79A. 2-(4-Chloro-phenyl)-2-(4-iodo-phenyl)-oxirane

Sodium hydride (60% dispersion in oil, 128 mg, 3.2 mmol) was placedunder N2 then DMSO (5 mL) was added. Trimethylsulfonium iodide (0.66 g,3.2 mmol) was added as a solid after 15 min, followed after a further 30min by (4-chloro-phenyl)-(4-iodo-phenyl)-methanone. The mixture wasstirred at room temperature for 24 hours then diluted with ethyl acetateand washed with 1:2 water/brine, water and brine (×2). The organic phasewas dried (MgSO₄), filtered and concentrated to give the title compound(1.01 g, 97%), which was used without further purification. LCMS (PS-A2)R_(t) 4.07 min [M−H]⁺ 355.

79B.1-(4-Chloro-phenyl)-2-(2-hydroxy-ethylamino)-1-(4-iodo-phenyl)-ethanol

A solution of 2-(4-chloro-phenyl)-2-(4-iodo-phenyl)-oxirane (0.60 g,1.68 mmol), ethanolamine (0.5 mL, 8.3 mmol) and triethylamine (0.5 mL,3.6 mmol) in iso-propanol (5 mL) was maintained at 50° C. for 72 hoursthen concentrated in vacuo. The residue was taken up in ethyl acetateand washed with saturated potassium carbonate solution/water (1:9). Theaqueous phase was extracted a second time with ethyl acetate, then thecombined extracts were washed with brine, dried (MgSO₄), filtered andconcentrated to give the title compound (701 mg, quantitative); LCMS(PS-A2) R_(t) 2.29 min [M+H]⁺ 418, [M−H₂O+H]⁺ 400.

79C. 2-(4-Chloro-phenyl)-2-(4-iodo-phenyl)-morpholine

A solution of1-(4-chloro-phenyl)-2-(2-hydroxy-ethylamino)-1-(4-iodo-phenyl)-ethanol(701 mg, 1.68 mmol) in DCM (10 mL) was treated with concentrated H₂SO₄(0.1 mL, 1.9 mmol). After 20 hours, another portion of H₂SO₄ (1.0 mL, 19mmol) was added and the mixture stirred for a further 2 hours. Themixture was diluted with ethyl acetate and washed with saturatedpotassium carbonate and brine then dried (MgSO₄), filtered andconcentrated. The residue was purified by column chromatography (SiO₂),eluting with 0.5% triethylamine in ethyl acetate to afford the titlecompound (290 mg, 43%); LCMS (PS-A2) R_(t) 2.40 min [M+H]⁺ 400.

79D. 2-(4-Chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-morpholine

2-(4-chloro-phenyl)-2-(4-Iodo-phenyl)morpholine was reacted with4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole followingthe procedure set out in Example 1, but usingtetrakis(triphenylphosphine)palladium (0) as the catalyst to give thetitle compound. LCMS (PS-A3) R_(t) 6.88 min [M+H^(+]) 340. ¹H NMR(Me-d₃-OD) δ 2.84-2.88 (2H, m), 3.32-3.36 (1H, m), 3.45-3.49 (1H, m),3.69-3.72 (2H, m), 7.31 (2H, d), 7.40 (4H, apparent d), 7.56 (2H, d),7.92 (2H, br.s).

Example 80(4-{4-[4-(1H-Pyrazol-4-yl)-phenyl]-piperidin-4-yl}-phenoxy)-acetic acidand (4-{4-[4-(1H-Pyrazol-4-yl)-phenyl]-piperidin-4-yl}-phenoxy)-aceticacid, methyl ester 80A.{4-[4-(4-bromo-phenyl)-piperidin-4-yl]-phenoxy}-acetic acid ethyl ester

By following the procedure described in Example 42B but substitutingchlorobenzene for ethyl phenoxyacetate and employing nitrobenzene assolvent, the title compound was obtained. LCMS (PS-A2) R_(t) 2.37 min[M+H]⁺ 418.

80B. (4-{4-[4-(1H-Pyrazol-4-yl)-phenyl]-piperidin-4-yl}-phenoxyl-aceticacid and(4-{4-[4-(1H-Pyrazol-4-yl)-phenyl]-piperidin-4-yl}-phenoxy)-acetic acid,methyl ester

{4-[4-(4-bromo-phenyl)-piperidin-4-yl]-phenoxy}-acetic acid ethyl esterwas reacted with4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole followingthe procedure set out in Example 1, but usingtetrakis(triphenylphosphine)palladium (0) as the catalyst and heating at80° C. for 30 minutes, to yield a mixture of the title compounds. Onwork up the basic aqueous extract was neutralised with hydrochloric acidand extracted with ethyl acetate (×2), then these organic extracts werecombined and washed with brine, dried (MgSO₄), filtered and concentratedto give a crude product that was recrystallised from water to afford(4-{4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidin-4-yl}-phenoxy)-acetic acid(12 mg, 5%); LCMS (PS-A3) R_(t) 5.33 min [M+H]⁺ 378. ¹H NMR (DMSO-d₆) δ2.22-2.26 (4H, m), 2.67-2.71 (4H, m), 4.65 (2H, s) 6.67 (2H, d), 7.11(2H, d), 7.24 (2H, d), 7.46 (2H, d), 7.96 (2H, br.s).

The material which was not extracted into base was converted on standingin methanol to a single compound,{4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidin-4-yl}-phenoxy)-acetic acid,methyl ester. This was purified by preparative HPLC to afford the titlecompound (18 mg, 7%); LCMS (PS-A3) R_(t) 6.13 min [M+H]⁺ 392. ¹H NMR(Me-d₃-OD) δ 2.34-2.45 (4H, m), 2.87 (4H, apparent t), 3.75 (3H, s),6.83 (2H, d), 7.21 (2H, d), 7.26 (2H, d), 7.47 (2H, d), 7.89 (2H, s).

Example 814-{4-[4-(1H-Pyrazol-4-yl)-phenyl]-piperidin-4-yl}-benzonitrile 81A.4-(4-Chloro-phenyl)-4-(4-iodo-phenyl)-piperidine

By following the procedure described in Example 42B but substitutingchlorobenzene for iodobenzene, the title compound was obtained. LCMS(PS-A2) 2.68 min [M+H]⁺ 398.

81B. 4-[4-(4-Chloro-phenyl)-piperidin-4-yl]-benzonitrile

A mixture of 4-(4-chloro-phenyl)-4-(4-iodo-phenyl)-piperidine and copper(I) cyanide in DMF was heated at 140° C. under nitrogen for 6 hours thenallowed to cool. The mixture was diluted with ethyl acetate, washed witha mixture of conc. ammonia and brine (×5), dried (MgSO₄), filtered andconcentrated to give a residue which was partially purified by columnchromatography (SiO₂), eluting with a gradient of 2M ammonia in methanol(5% to 10%) and dichloromethane to afford the title compound (46 mg,<16%). This was taken on to the next reaction without furtherpurification. LCMS (PS-A2) R_(t) 2.39 min [M+H]⁺ 297.

81C. 4-{4-[4-(1H-Pyrazol-4-yl)-phenyl]-piperidin-4-yl}-benzonitrile

4-[4-(4-chloro-phenyl)-piperidin-4-yl]-benzonitrile was reacted with4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole followingthe procedure set out in Example 1, but usingtetrakis(triphenylphosphine)palladium (0) as the catalyst and heating at100° C. for 15 minutes, to obtain the title compound. LCMS (PS-A3) R_(t)6.68 min [M+H]⁺ 329. ¹H NMR (Me-d₃-OD) δ 2.65-2.73 (4H, m), 2.77-2.85(4H, m), 3.75 (3H, s), 7.46 (2H, d), 7.59 (2H, d), 7.68 (2H, d), 7.71(2H, d), 8.42 (2H, br.s).

Example 82{2-(4-Chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-propyl}-methyl-amine82A. Bis-(4-chloro-phenyl)-acetic acid methyl ester

Bis-(4-chloro-phenyl)-acetic acid (4.33 g, 15.4 mmol) was suspended inanhydrous methanol (20 mL) and concentrated hydrochloric acid (5 drops)was added. After 1 day the reaction was quenched by the addition ofsaturated sodium bicarbonate solution, then the organic solvent wasremoved in vacuo. The residue was partitioned between ethyl acetate and50% saturated potassium carbonate solution. The organic phase was washedwith brine, dried (MgSO₄), filtered and concentrated to give a residuewhich was purified by column chromatography (SiO₂), eluting with 10%ethyl acetate/petrol, to afford the title compound as a colourless oil(3.57 g, 78%); LCMS (PS-B3) R_(t) 3.79 min, No ionisation. ¹H NMR(CDCl₃) δ 3.74 (3H, s), 4.96 (1H, s), 7.20-7.23 (4H, m), 7.28-7.32 (4H,m).

82B. 2,2-Bis-(4-chloro-phenyl)-propionic acid methyl ester

A solution of bis-(4-chloro-phenyl)-acetic acid methyl ester (1.19 g,4.0 mmol) in THF (20 ml) was cooled to −78° C. under nitrogen. Asolution of LDA (3.0 mL, 6.0 mmol, 2M in heptane/THF/ethylbenzene) wasadded over 5 minutes, then after a further 20 minutes, iodomethane (0.63ml, 10.1 mmol) was added. After 4 hours the reaction was quenched by theaddition of saturated ammonium chloride solution and allowed to warm toroom temperature then concentrated in vacuo to remove organic solvents.The mixture was diluted with ethyl acetate/petrol 1:4 and washed withsaturated ammonium chloride solution then brine, dried (MgSO₄), filteredand concentrated to give a residue which was purified by columnchromatography (SiO₂), eluting with an ethyl acetate/petrol gradient (1%to 2%), to afford the title compound as a colourless oil (210 mg, 17%);LCMS (PS-B3) R_(t) 4.01 min, No ionisation. ¹H NMR (CDCl₃) δ 1.88 (3H,s), 3.73 (3H, 5), 7.11-7.14 (4H, m), 7.26-7.30 (4H, m).

82C. 2,2-Bis-(4-chloro-phenyl)-propionic acid

A solution of 2,2-bis-(4-chloro-phenyl)-propionic acid methyl ester (210mg, 0.67 mmol) in THF/water/methanol (1:1:1, 18 mL) was stirred at roomtemperature for 5 days then concentrated in vacuo. The residue waspartitioned between ethyl acetate and 2N hydrochloric acid, then theorganic phase was washed with brine, dried (MgSO₄), filtered andconcentrated to give the title compound (186 mg, 93%) as a yellow solidwhich was used without further purification. LCMS (PS-B3) R_(t) 2.40 min[M-CO₂H]⁻ 249.

82D. 2,2-Bis-(4-chloro-phenyl)-N-methyl-propionamide

By following the procedure described in Example 8D but substituting3-(4-bromo-phenyl)-3-(4-chloro-phenyl)-propionic acid for2,2-bis-(4-chloro-phenyl)-propionic acid, the title compound wasobtained. LCMS (PS-B3) R_(t) 3.40 min [M+H]⁺ 308.

82E. [2,2-Bis-(4-chloro-phenyl)-propyl]-methyl-amine

By following the procedure described in Example 8E but substituting3-(4-Bromo-phenyl)-3-(4-chloro-phenyl)-N-methyl-propionamide for2,2-Bis-(4-chloro-phenyl)-N-methyl-propionamide, the title compound wasobtained. LCMS (FL-A) R_(t) 2.35 min [M+H]⁺ 294

82F.{2-(4-Chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-propyl}-methyl-amine

[2,2-Bis-(4-chloro-phenyl)-propyl]-methyl-amine was reacted with4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole followingthe procedure set out in Example 1 to give the title compound. LCMS(PS-A3) R_(t) 6.94 min [M+H]⁺ 326. ¹H NMR (Me-d₃-OD) δ 1.86 (3H, s),2.77 (3H, s), 3.89 (2H, s), 7.26-7.33 (4H, m), 7.37-7.40 (2H, m), 7.68(2H, d), 8.35 (2H, s).

Example 831-(4-Chloro-phenyl)-2-methylamino-1-[4-(1H-pyrazol-4-yl)-phenyl]-ethanol

By following the procedure described in Example 79A, 79B and 79D butsubstituting ethanolamine for methylamine, the title compound wasobtained. LCMS (PS-A3) R_(t) 5.28 min [M+H]⁺ 328, [M−H₂O+H]⁺ 310. ¹H NMR(Me-d₃-OD) δ 2.38 (3H, s), 3.34 (2H, s), 7.28-7.31 (2H, m), 7.41-7.46(4H, m), 7.51-7.54 (2H, m), 7.92 (2H, s).

Example 842-Amino-1-(4-chloro-phenyl)-1-[4-(1H-pyrazol-4-yl)-phenyl]-ethanol 84A.2-[2-(4-Chloro-phenyl)-2-hydroxy-2-(4-iodo-phenyl)-ethyl]-isoindole-1,3-dione

A mixture of 2-(4-chloro-phenyl)-2-(4-iodo-phenyl)-oxirane* (571 mg,1.60 mmol) and potassium phthalimide (340 mg, 1.84 mmol) in THF (5 mL)and DMSO (2 mL) was heated at 100° C. for 20 hours. The mixture wasconcentrated in vacuo, diluted with ethyl acetate and washed with waterand brine (×2), dried (MgSO₄), filtered and concentrated to give a crudeproduct which was purified by column chromatography (SiO₂), eluting witha gradient of ethyl acetate/petrol (2.5% to 100%) then 10%methanol/dichloromethane to give the title compound (273 mg, 34%); LCMS(PS-A2) R_(t) 3.22 min [M+H]⁺ 504.

* This starting material can be made by the method described in Example79A

84B.N-{2-(4-Chloro-phenyl)-2-hydroxy-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-phthalamicacid

2-[2-(4-Chloro-phenyl)-2-hydroxy-2-(4-iodo-phenyl)-ethyl]-isoindole-1,3-dionewas reacted with4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole followingthe procedure set out in Example 1, but usingtetrakis(triphenylphosphine)palladium (0) as the catalyst, to obtain thetitle compound. LCMS (PS-A2) R_(t) 2.62 min [M−H]⁻ 460.

84C. 2-Amino-1-(4-chloro-phenyl)-1-[4-(1H-pyrazol-4-yl)-phenyl]-ethanol

By following the procedure described in Example 49D but substitutingN-(2-{(4-Chloro-phenyl)-[4-(1H-pyrazol-4-yl)-phenyl]-methoxy}-ethyl)-phthalamicacid forN-{2-(4-Chloro-phenyl)-2-hydroxy-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-phthalamicacid, the title compound was obtained. LCMS (PS-A3) R_(t) 6.29 min[M−H₂O+H]⁺ 296. ¹H NMR (Me-d₃-OD) δ 3.29-3.38 (2H, m), 7.32 (2H, d),7.41-7.46 (4H, m), 7.55 (2H, d), 7.94 (2H, s).

Example 854-(3,4-Dichloro-phenyl)-4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidine

By following the procedure described in Example 14 but substitutingchlorobenzene for 1,2-dichlorobenzene, the title compound was obtained.LCMS (PS-B4) R_(t) 7.20 min [M+H]⁺ 372. ¹H NMR (Me-d₃-OD) δ 2.62-2.69(2H, m), 2.73-2.81 (2H, m), 3.18-3.30 (4H, m), 7.34 (1H, dd), 7.46-7.52(3H, m), 7.53 (1H, d), 7.72 (2H, d), 8.56 (2H, s).

Example 864-(3-Chloro-4-methoxy-phenyl)-4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidine

By following the procedure described in Example 14 but substitutingchlorobenzene for 2-chloroanisole, the title compound was obtained. LCMS(PS-B4) R_(t) 6.24 min [M+H]⁺ 368. ¹H NMR (Me-d₃-OD) δ 2.62-2.75 (4H,m), 3.23 (4H, apparent t), 3.86 (3H, s), 7.06 (1H, d), 7.30 (1H, dd),7.34 (1H, d), 7.45 (2H, d), 7.69 (2H, d), 8.57 (2H, s).

Example 874-(4-Chloro-3-fluoro-phenyl)-4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidine87A. 4-(4-Chloro-3-fluoro-phenyl)-4-hydroxy-piperidine-1-carboxylic acidtert-butyl ester

A solution of 4-chloro-3-fluorophenylmagnesium bromide (15 ml, 7.5 mmol,0.5M in THF) was added, under nitrogen, to 4-oxo-piperidine-1-carboxylicacid tert-butyl ester (1.02 g, 5.1 mmol). After 24 hours, saturatedammonium chloride solution was added then the organic solvent wasremoved in vacuo. The mixture was extracted with ethyl acetate, thenthis extract was washed with brine, dried (MgSO₄), filtered andconcentrated to afford a residue which was purified by columnchromatography (SiO₂), eluting with gradient of ethyl acetate/petrol (0%to 20%) to afford the title compound (511 mg, 30%). ¹H NMR (Me-d₃-OD) δ1.48 (9H, s), 1.67 (2H, br.d), 1.92 (2H, td), 3.16-3.29 (2H, m), 3.99(2H, br.d), 7.27 (1H, dd), 7.38 (1H, dd), 7.42 (1H, t).

87B. 4-(4-Bromo-phenyl)-4-(4-chloro-3-fluoro-phenyl)-piperidine

By following the procedure described in Example 42B but substitutingchlorobenzene for bromobenzene, the title compound was obtained. LCMS(PS-A2) R_(t) 2.43 min [M+H]⁺ 368.

87C.4-(4-Chloro-3-fluoro-phenyl)-4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidine

4-(4-Bromo-phenyl)-4-(4-chloro-3-fluoro-phenyl)-piperidine was reactedwith 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolefollowing the procedure set out in Example 1, but usingtetrakis(triphenylphosphine)palladium (0) as the catalyst, to obtain thetitle compound. LCMS (PS-A3) R_(t) 7.11 min [M+H]⁺ 356. ¹H NMR(Me-d₃-OD) δ 2.62-2.80 (4H, m), 3.18-3.30 (partially overlaps withsolvent, 4H, m), 7.23 (1H, t), 7.34-7.39 (1H, m), 7.22 (1H, dd), 7.30(1H, dd), 7.43-7.49 (3H, m), 7.71 (2H, d), 8.55 (2H, s).

Example 88 4-{4-[4-(1H-Pyrazol-4-yl)-phenyl]-piperidin-4-yl}-benzoicacid 88A.4-(4-carboxy-phenyl)-4-(4-chloro-phenyl)-piperidine-1-carboxylic acidtert-butyl ester

Under nitrogen, a solution of4-(4-bromo-phenyl)-4-(4-chloro-phenyl)piperidine-1-carboxylic acidtert-butyl ester* (888 mg, 1.97 mmol) in THF (5 mL) was cooled to −78°C. A solution of n-butyllithium (1.5 mL, 1.6M in hexanes) was addeddropwise and the mixture maintained at this temperature for 25 minutes.Carbon dioxide gas (generated from dry ice and dried by passage througha column of calcium chloride pellets) was bubbled through the anionsolution for 80 minutes then the mixture was allowed to warm to roomtemperature. The solvents were removed in vacuo then the residue waspartitioned between 1N hydrochloric acid and diethyl ether. The organicphase was separated, dried (MgSO₄), filtered and concentrated. Thecombined aqueous phases were further extracted with ethyl acetate, thisextract also being dried (MgSO₄), filtered, combined with the etherealextract and concentrated to afford4-(4-carboxy-phenyl)-4-(4-chloro-phenyl)-piperidine-1-carboxylic acidtert-butyl ester (889 mg); LCMS (PS-A2) R_(t) 3.52 min [M-^(t)Bu+H]⁺360.

* This starting material can be made by the method described in Example14A followed by Example 48A

88B.4-(4-Carboxy-phenyl)-4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidine-1-carboxylicacid tert-butyl ester

4-(4-Carboxy-phenyl)-4-(4-chloro-phenyl)-piperidine-1-carboxylic acidtert-butyl ester was reacted with4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole followingthe procedure set out in Example 1, to obtain the title compound. LCMS(PS-A2) R_(t) 2.92 min [M+H]⁺ 448.

88C. 4-{4-[4-(1H-Pyrazol-4-yl)-phenyl]-piperidin-4-yl}-benzoic acid

4-(4-Carboxy-phenyl)-4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidine-1-carboxylicacid tert-butyl ester (26 mg, 0.06 mmol) was dissolved in dioxane (2 mL)and 1N hydrochloric acid (2 mL). After 24 hours the mixture wasconcentrated in vacuo and triturated with diethyl ether to afford thetitle compound as the dihydrochloride salt (22 mg, 90%); LCMS (PS-A3)R_(t) 5.22 min [M+H]⁺ 348. ¹H NMR (Me-d₃-OD) δ 2.70-2.82 (4H, m), 3.26(4H, apparent t), 7.46 (2H, d), 7.51 (2H, m), 7.68 (2H, d), 8.00 (2H,d), 8.47 (2H, s).

Example 894-[4-(1H-Pyrazol-4-yl)-phenyl]-1,2,3,4,5,6-hexahydro-[4,4′]bipyridinyl89A.4-(4-Chloro-phenyl)-3,4,5,6-tetrahydro-2H-[4,4′]bipyridinyl-1-carboxylicacid tert-butyl ester

Under nitrogen, a solution of bis-(2-chloro-ethyl)-carbamic acidtert-butyl ester* (1.54 g, 6.36 mmol) in toluene (10 mL) was cooled inice. 4-(4-Chloro-benzyl)-pyridine (1.30 g, 6.36 mmol) was added,followed over two minutes by sodium hexamethyldisilazide solution (10mL, 20 mmol, 2M in THF). The mixture was stirred at 0° C. for 3.5 hoursthen allowed to warm to room temperature and stirred for a further 20hours. Methanol was added then the mixture was concentrated in vacuo.The residue was taken up in ethyl acetate and washed with 1Nhydrochloric acid (×3) and brine, dried (MgSO₄), filtered andconcentrated to afford a residue which was purified by columnchromatography (SiO₂), eluting with gradient of 2M methanolic ammonia indichloromethane (1% to 5%). A second purification by columnchromatography (SiO₂), eluting with 50% ethyl acetate/petrol gave thetitle compound (16 mg, 0.7%). LCMS (PS-A2) R_(t) 2.65 min [M+H]⁺ 373.

* This starting material can be made by the method described in J. Chem.Soc., Perkin Trans 1, 2000, p 3444-3450

89B.4-[4-(1H-Pyrazol-4-yl)-phenyl]-1,2,3,4,5,6-hexahydro-[4,4′]bipyridinyl

4-(4-Chloro-phenyl)-3,4,5,6-tetrahydro-2H-[4,4′]bipyridinyl-1-carboxylicacid tert-butyl ester was reacted with4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole followingthe procedure set out in Example 1, followed by treatment with 4M HCl indioxane, to obtain the title compound. LCMS (PS-B4) R_(t) 4.28 min[M+H]⁺ 305. ¹H NMR (Me-d₃-OD) δ 2.76 (2H, br.t), 3.01 (2H, br.d), 3.24(2H, br.t), 3.39 (2H, br.d), 7.58 (2H, d), 7.76 (2H, d), 8.17 (2H, d),8.37 (2H, s), 8.82 (2H, d).

Example 903-(3-Chloro-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propylamine

By following the procedure described in Example 8 but substituting4-chlorophenylmagnesium bromide for 3-chlorophenylmagnesium bromide andmethylamine for ammonia the title compound was obtained. LCMS (PS-B3)R_(t) 2.60 min [M+H]⁺ 312. ¹H NMR (Me-d₃-OD) δ 2.44 (2H, apparent qd),2.87 (2H, dd), 4.14 (1H, t), 7.24 (1H, dt), 7.27-7.33 (2H, m), 7.34 (1H,t), 7.42 (2H, d), 7.68 (2H, d), 8.58 (2H, s).

Example 912-Methylamino-1-(4-nitro-phenyl)-1-[4-(1H-pyrazol-4-yl)-phenyl]-ethanol

By following the procedure described in Example 83 but substituting(4-chloro-phenyl)-(4-iodo-phenyl)-methanone for(4-Bromo-phenyl)-(4-nitro-phenyl)-methanone, the title compound wasobtained. LCMS (PS-A) R_(t) 1.79 [M+H]⁺ 339. ¹H NMR (Me-d₃-OD) δ 8.27(2H, d), 7.98 (2H, s), 7.80 (2H, d), 7.65 (2H, d), 7.52 (2H, d), 4.00(2H, dd), 2.73 (3H, s)—CH(OH) signal presumed to be under water peak.

Example 922-(3-Chloro-4-methoxy-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethylamine

By following the procedure described in Example 87B and Example 42C butreplacing 1-(4-bromo-phenyl)-2-methylamino-ethanol with2-amino-1-(4-bromo-phenyl)-ethanol and chlorobenzene with2-chloroanisole, the title compound was obtained. LCMS (PS-B3) R_(t)2.55 [M+H]⁺ 328.20. ¹H NMR (Me-d₃-OD) δ 3.65-3.70 (2H, d), 3.90 (3H, s),4.30-4.35 (1H, t), 7.05-7.10 (1H, d), 7.30-7.35 (1H, d), 7.40 (1H, s),7.45-7.50 (2H, d), 7.70-7.75 (2H, d), 8.60 (2H, s).

Example 932-(4-Chloro-phenyl)-2-fluoro-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethylamine93A. 2,2-Bis-(4-chloro-phenyl)-2-fluoro-ethylamine

2-Amino-1,1-bis-(4-chloro-phenyl)-ethanol (293 mg, 1.04 mmol) wasdissolved in pyridine-HF (2 ml) with cooling. After 24 hours the mixturewas diluted into 1N sodium hydroxide solution and extracted with DCM(×3). Each extract was dried (MgSO₄) and filtered before being combinedand concentrated to give a residue which was purified by columnchromatography (SiO₂), eluting with 0.5% triethylamlne in ethyl acetateto afford the title compound (192 mg, 65%); LCMS (PS-B3) R_(t) 3.34 min[M-F⁻]⁺ 266. ¹H NMR (DMSO-d₆) δ 3.41 (2H, d), 7.39-7.46 (8H, m).

93B.2-(4-Chloro-phenyl)-2-fluoro-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethylamine

2,2-Bis-(4-chloro-phenyl)-2-fluoro-ethylamine was reacted with4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole followingthe procedure set out in Example 1 except that heating was carried outat 100° C. for 5 minutes using 300 W power in a CEM microwave, to obtainthe title compound. LCMS (PS-B4) R_(t) 6.69 min [M-F⁻]⁺ 296. ¹H NMR(Me-d₃-OD) δ 4.04 (2H, d), 7.47-7.55 (6H, m), 7.77 (2H, d), 8.41 (2H,d).

Example 943-(3,4-Dichloro-phenyl)-3-[6-(1H-pyrazol-4-yl)-pyridin-3-yl]-propylamine

By following the procedure described in Example 60 but replacing6-chloro-nicotinonitrile with 6-chloro-pyridine-3-carbaldehyde andreplacing 3-methyl-1-trityl-1H-pyrazole-4-boronic acid with1-trityl-1H-pyrazole-4-boronic acid, and then following the proceduredescribed in Example 8, the title compound could be obtained.

Example 952-(4-Chloro-3-fluoro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethylamine

By following the procedure described in Example 87, but replacing4-oxo-piperidine-1-carboxylic acid tert-butyl ester with(2-oxo-ethyl)-carbamic acid tert-butyl ester, the title compound couldbe obtained.

Example 964-(2-Chloro-3-fluoro-phenyl)-4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidine

By following the procedure described in Example 14, but replacingchlorobenzene with 1-chloro-2-fluorobenzene, the title compound can beobtained.

Example 971-{(3,4-Dichloro-phenyl)-[4-(1H-pyrazol-4-yl)-phenyl]-methyl}-piperazine97A. (4-Chloro-phenyl)-(3,4-dichloro-phenyl)-methanol

Commercially available chlorophenyl magnesium bromide and3,4-dichlorobenzaldehyde can be reacted together according to the methoddescribed in J. Medicinal Chem., (2000), 43(21), 3878-3894 to give thetitle compound.

97B. 1,2-Dichloro-4-[chloro-(4-chloro-phenyl)-methyl]-benzene

The product of Example 97A can be reacted with SO₂Cl₂ according to themethod described in Organic Letters, (2003), 5(8), 1167-1169 to give thetitle compound.

97C.1-{(3,4-Dichloro-phenyl)-[4-(1H-pyrazol-4-yl)-phenyl]-methyl}-piperazine

The title compound may be prepared from the compound of Example 97C byusing the method and conditions described in Zhongguo Yaowu Huaxue Zazhi(2002), 12(3), 125-129.

Example 982-(3,4-Dichloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethylamine

By following the procedure described in Example 42 but, in Example 42B,replacing chlorobenzene with 1,2-dichloro-benzene, the title compoundcan be obtained

Example 99{2-(3-Chloro-4-methoxy-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-methyl-amine

By following the procedure described in Example 42 but, in step 42B,substituting 2-chloroanisole for chlorobenzene, the title compound wasobtained. LC/MS: (PS-A2) R_(t) 2.03 [M+H]⁺ 342. ¹H NMR (Me-d₃-OD) 2.45(3H, s), 3.22 (2H, d), 3.85 (3H, s), 4.15 (1H, t), 7.04 (1H, d), 7.33(1H, d), 7.27-7.34 (3H, m), 7.55 (2H, d), 7.92 (2H, s).

Example 1004-{4-[2-Azetidin-1-yl-1-(4-chloro-phenoxy)-ethyl]-phenyl}-1H-pyrazole

By following the procedure described in Example 42A, but replacingmethylamine with azetidine and following the procedure in Example 45,the title compound could be obtained

Example 1013-(3-Chloro-4-methoxy-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propylamine

By following the procedure described in Example 61, but replacingimidazole with potassium phthalimide in step 61A and replacingchlorobenzene with 1-chloro-2-methoxy-benzene in 61B, and then removingthe phthaloyl protecting group under the conditions set out in Examples84B and 84C, the title compound may be prepared.

Example 102{3-(3-Chloro-4-methoxy-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propyl}-methyl-amine

By following the procedure described in Example 61, but substitutingimidazole with methylamine in Example 61A and substituting chlorobenzenewith 1-chloro-2-methoxy-benzene in Example 61B, the title compound maybe obtained.

Example 1031-[(3-Chloro-4-methoxy-phenyl)-(4-chloro-phenyl)-methyl]-piperazine103A. (3-Chloro-4-methoxy-phenyl)-(4-chloro-phenyl)-methanol

The title compound can be prepared using the method of Example 97A butreplacing 3,4-dichlorobenzaldehyde with 3-chloro-4-methoxybenzaldehyde.

103B. 2-Chloro-4-[chloro-(4-chloro-phenyl)-methyl]-1-methoxy-benzene

The hydroxy compound of Example 103A can be converted into the titlechloro compound by following the method of Example 97B.

103C.1-[(3-Chloro-4-methoxy-phenyl)-(4-chloro-phenyl)-methyl]-piperazine

The title compound can be prepared from the product of Example 103B byfollowing the method of Example 97C.

Example 104C-(4-Chloro-phenyl)-C-[4-(1H-pyrazol-4-yl)-phenyl]-methylamine

By following the procedure described in Example 1 but substituting2-(4-chlorophenyl)-2-phenylethylamine hydrochloride withC,C-bis-(4-chloro-phenyl)-methylamine, the title compound could beobtained.

Example 105{2-(4-Chloro-phenyl)-2-[4-(3-methyl-1H-pyrazol-4-yl)-phenyl]-ethyl}-methyl-amine105A.2-(4-Chloro-phenyl)-N-methyl-2-[4-(3-methyl-1-trityl-1H-pyrazol-4-yl)-phenyl]-acetamide

2,2-Bis-(4-chloro-phenyl)-N-methyl-acetamide was prepared by thereaction of the commercially available corresponding carboxylic acidwith methylamine using the method of Example 21a. The N-methyl-acetamidecompound was then converted to the title compound by the methoddescribed in Example 1.

LCMS (PS-B3) R_(t) 4.21 min; m/z [M+H]⁺ 582.

105B.2-(4-Chloro-phenyl)-N-methyl-2-[4-(3-methyl-1H-pyrazol-4-yl)-phenyl]-acetamide

The trityl-protected compound of example 104A was deprotected by themethod described in example 60D to give the title compound.

LCMS (PS-B3) R_(t) 2.41 min; m/z [M+H]⁺ 340. ¹H NMR (methanol-d₄) δ 2.40(3H, s), 2.78 (3H, s), 4.95 (1H, s), 7.29-7.34 (6H, m), 7.41 (2H, d),7.69 (1H, s).

105C.{2-(4-Chloro-phenyl)-2-[4-(3-methyl-1H-pyrazol-4-yl)-phenyl]-ethyl}-methyl-amine

Following the procedure described in example 20B gave the titlecompound.

LCMS (PS-B3) R_(t) 2.80 min; m/z [M+H]⁺ 326. ¹H NMR (methanol-d₄) δ 2.52(3H, s), 2.75 (3H, s), 3.80 (2H, d), 4.46 (1H, t), 7.41 (4H, s), 7.49(2H, d), 7.54 (2H, d), 8.24 (1H, s).

Biological Activity Example 106 Measurement of PKA Kinase InhibitoryActivity (IC₅₀)

Compounds of the invention can be tested for PK inhibitory activityusing the PKA catalytic domain from Upstate Biotechnology (#14-440) andthe 9 residue PKA specific peptide (GRTGRRNSI), also from UpstateBiotechnology (#12-257), as the substrate. A final concentration of 1 nMenzyme is used in a buffer that includes 20 mM MOPS pH 7.2, 40 μMATP/γ³³P-ATP and 5 μM substrate. Compounds are added indimethylsulphoxide (DMSO) solution to a final DMSO concentration of2.5%. The reaction is allowed to proceed for 20 minutes before additionof excess orthophosphoric acid to quench activity. Unincorporatedγ³³P-ATP is then separated from phosphorylated proteins on a MilliporeMAPH filter plate. The plates are washed, scintillant is added and theplates are then subjected to counting on a Packard Topcount.

The % inhibition of the PKA activity is calculated and plotted in orderto determine the concentration of test compound required to inhibit 50%of the PKB activity (IC₅₀).

The compounds of Examples 1, 4, 43, 44, 45, 46, 47, 48, 49, 52, 54, 59,63, 66, 67, 73, 78, 79, 81, 82, 83, 84, 85, 86 and 90 have IC₅₀ valuesof less than 1 μM whereas the compounds of Examples 5, 7 and 80 haveIC₅₀ values of less than 15 μM.

Example 107 Measurement of PKB Kinase Inhibitory Activity (IC₅₀)

The inhibition of protein kinase B (PKB) activity by compounds can bedetermined determined essentially as described by Andjelkovic et al.(Mol. Cell. Biol. 19, 5061-5072 (1999)) but using a fusion proteindescribed as PKB-PIF and described in full by Yang et al (NatureStructural Biology 9, 940-944 (2002)). The protein is purified andactivated with PDK1 as described by Yang et al. The peptide AKTide-2T(H-A-R-K-R-E-R-T-Y-S-F-G-H-H-A-OH) obtained from Calbiochem (#123900) isused as a substrate. A final concentration of 0.6 nM enzyme is used in abuffer that includes 20 mM MOPS pH 7.2, 30 μM ATP/γ³³P-ATP and 25 μMsubstrate. Compounds are added in DMSO solution to a final DMSOconcentration of 2.5%. The reaction is allowed to proceed for 20 minutesbefore addition of excess orthophosphoric acid to quench activity. Thereaction mixture is transferred to a phosphocellulose filter plate wherethe peptide binds and the unused ATP is washed away. After washing,scintillant is added and the incorporated activity measured byscintillation counting.

The % inhibition of the PKB activity is calculated and plotted in orderto determine the concentration of test compound required to inhibit 50%of the PKB activity (IC₅₀).

Following the protocol described above, the IC₅₀ values of the compoundsof Examples 1, 4, 8-10, 12-17, 20-23, 25-31, 33-35, 43, 44, 46, 47,49-52, 54, 56, 57, 59, 61, 63, 65, 66, 69, 71-73, 76-79, 81-87, 90, 91,94 and 104 have been found to be less than 1 μM whilst the compounds ofExamples 2, 3, 5, 6, 7, 11, 18, 19, 24, 32, 36, 45, 48, 53, 55, 58, 60,64, 67, 68, 75, 80 and 89 each have IC₅₀ values of less than 5 μM, andthe compounds of Examples 40, 41, 62 and 70 each have IC₅₀ values ofless than 50 μM.

Example 108 Pharmaceutical Formulations

(i) Tablet Formulation

A tablet composition containing a compound of the formula (I) isprepared by mixing 50 mg of the compound with 197 mg of lactose (BP) asdiluent, and 3 mg magnesium stearate as a lubricant and compressing toform a tablet in known manner.

(ii) Capsule Formulation

A capsule formulation is prepared by mixing 100 mg of a compound of theformula (I) with 100 mg lactose and filling the resulting mixture intostandard opaque hard gelatin capsules.

(iii) Injectable Formulation I

A parenteral composition for administration by injection can be preparedby dissolving a compound of the formula (I) (e.g. in a salt form) inwater containing 10% propylene glycol to give a concentration of activecompound of 1.5% by weight. The solution is then sterilised byfiltration, filled into an ampoule and sealed.

(iv) Injectable Formulation II

A parenteral composition for injection is prepared by dissolving inwater a compound of the formula (I) (e.g. in salt form) (2 mg/ml) andmannitol (50 mg/ml), sterile filtering the solution and filling intosealable 1 ml vials or ampoules.

v) Injectable Formulation III

A formulation for i.v. delivery by injection or infusion can be preparedby dissolving the compound of formula (I) (e.g. in a salt form) in waterat 20 mg/ml. The vial is then sealed and sterilised by autoclaving.

vi) Injectable Formulation IV

A formulation for i.v. delivery by injection or infusion can be preparedby dissolving the compound of formula (I) (e.g. in a salt form) in watercontaining a buffer (e.g. 0.2 M acetate pH 4.6) at 20 mg/ml. The vial isthen sealed and sterilised by autoclaving.

(vii) Subcutaneous Injection Formulation

A composition for sub-cutaneous administration is prepared by mixing acompound of the formula (I) with pharmaceutical grade corn oil to give aconcentration of 5 mg/ml. The composition is sterilised and filled intoa suitable container.

viii) Lyophilised Formulation

Aliquots of formulated compound of formula (I) are put into 50 ml vialsand lyophilized. During lyophillsation, the compositions are frozenusing a one-step freezing protocol at (−45° C.). The temperature israised to −10° C. for annealing, then lowered to freezing at −45° C.,followed by primary drying at +25° C. for approximately 3400 minutes,followed by a secondary drying with increased steps if temperature to50° C. The pressure during primary and secondary drying is set at 80millitor.

Example 109 Assay for Therapeutic Efficacy

The effect of a compound of formula I (Compound I) in combination withan ancillary compound (Compound II) was assessed using the followingtechnique:

IC₅₀ Shift Assay

Cells from human cells lines (e.g. HCT116, MDA-MB-468, SKBr3 or coloncarcinoma cell line HT29 (ECACC No. 91072201)) were seeded onto 96-welltissue culture plates at a concentration of 5×10³ cells/well. Cells wereallowed to recover overnight prior to addition of compound(s) or vehiclecontrol (1% DMSO) as follows:

Compounds were added according to one of the following schedules;

-   -   a) Concurrent for 72 hours.    -   b) Compound I for 24 hours followed by Compound II for 48 hours.    -   c) Compound II for 24 hours followed by Compound I for 48 hours.

For example, in the following case compounds were added concurrently for72 hours. Following a total of 72 hours compound incubation, AlamarBlue™ was added to a final concentration of 10% (v/v) and incubated at37° C. for 6 hours. Fluorescent product was quantified by reading atd535/25× (excitation) and d590/20m (emission) on a Fusion Reader (PerkinElmer). The IC₅₀ for Compound II in the presence of varying doses ofCompound I was determined. Synergy was determined when the IC₅₀ shifteddown in the presence of sub-effective doses of Compound I. Additivitywas determined when the response to Compound II and Compound I togetherresulted in an effect equivalent to the sum of the two compoundsindividually. Antagonistic effects were defined as those causing theIC₅₀ to shift upwards, i.e. those where the response to the twocompounds was less than the sum of the effect of the two compoundsindividually.

The above assay can be run with any ancillary compound (for example,with a cytotoxic compound or monoclonal antibody). For example, it wasrun using 4-(4-Chloro-phenyl)-4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidine(see Example 14) as compound I and gefitinib (commercially availablefrom AstraZeneca plc under the trade name Iressa) as compound II. Theresults are shown in FIG. 1.

EQUIVALENTS

The foregoing examples are presented for the purpose of illustrating theinvention and should not be construed as imposing any limitation on thescope of the invention. It will readily be apparent that numerousmodifications and alterations may be made to the specific embodiments ofthe invention described above and illustrated in the examples withoutdeparting from the principles underlying the invention. All suchmodifications and alterations are intended to be embraced by thisapplication.

The invention claimed is:
 1. A combination comprising an ancillarycompound and a compound of the formula (I):

or a salt, solvate, tautomer or N-oxide thereof; wherein A is asaturated hydrocarbon linker group containing from 1 to 7 carbon atoms,the linker group having a maximum chain length of 5 atoms extendingbetween R¹ and NR²R³ and a maximum chain length of 4 atoms extendingbetween E and NR²R³, wherein one of the carbon atoms in the linker groupmay optionally be replaced by an oxygen or nitrogen atom; and whereinthe carbon atoms of the linker group A may optionally bear one or moresubstituents selected from oxo, fluorine and hydroxy, provided that thehydroxy group when present is not located at a carbon atom α withrespect to the NR²R³ group and provided that the oxo group when presentis located at a carbon atom α with respect to the NR²R³ group; E isphenyl or pyridine wherein E is unsubstituted or has up to 4substituents R⁸ selected from hydroxy, chlorine, bromine,trifluoromethyl, cyano, C₁₋₄ hydrocarbyloxy optionally substituted byC₁₋₂ alkoxy or hydroxy, and C₁₋₄ hydrocarbyl optionally substituted byC₁₋₂ alkoxy or hydroxy; R¹ is phenyl or pyridine which is unsubstitutedor bears one or more substituents selected from hydroxy; C₁₋₄ acyloxy;fluorine; chlorine; bromine; trifluoromethyl; cyano; CONH₂; nitro; C₁₋₄hydrocarbyloxy and C₁₋₄ hydrocarbyl each optionally substituted by C₁₋₂alkoxy, carboxy or hydroxy; C₁₋₄ acylamino; benzoylamino;pyrrolidinocarbonyl; piperidinocarbonyl; morpholinocarbonyl;piperazinocarbonyl; five and six membered heteroaryl and heteroaryloxygroups containing one or two heteroatoms selected from N, O and S;phenyl; phenyl-C₁₋₄ alkyl; phenyl-C₁₋₄ alkoxy; heteroaryl-C₁₋₄ alkyl;heteroaryl-C₁₋₄ alkoxy and phenoxy, wherein the heteroaryl,heteroaryloxy, phenyl, phenyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkoxy,heteroaryl-C₁₋₄ alkyl, heteroaryl-C₁₋₄ alkoxy and phenoxy groups areeach optionally substituted with 1, 2 or 3 substituents selected fromC₁₋₂ acyloxy, fluorine, chlorine, bromine, trifluoromethyl, cyano,CONH₂, C₁₋₂ hydrocarbyloxy and C₁₋₂ hydrocarbyl each optionallysubstituted by methoxy or hydroxy; R² and R³ are independently selectedfrom hydrogen, C₁₋₄ hydrocarbyl and C₁₋₄ acyl wherein the hydrocarbyland acyl moieties are optionally substituted by one or more substituentsselected from fluorine, hydroxy, amino, methylamino, dimethylamino andmethoxy; or R² and R³ together with the nitrogen atom to which they areattached form a cyclic group selected from an imidazole group and asaturated monocyclic heterocyclic group having 4-7 ring members andoptionally containing a second heteroatom ring member selected from Oand N; or one of R² and R³ together with the nitrogen atom to which theyare attached and one or more atoms from the linker group A form asaturated monocyclic heterocyclic group having 4-7 ring members andoptionally containing a second heteroatom ring member selected from Oand N; or NR²R³ and the carbon atom of linker group A to which it isattached together form a cyano group; R⁴ is selected from hydrogen,halogen, C₁₋₅ saturated hydrocarbyl, C₁₋₅ saturated hydrocarbyloxy,cyano, and CF₃; and R⁵ is selected from hydrogen, halogen, C₁₋₅saturated hydrocarbyl, C₁₋₅ saturated hydrocarbyloxy, cyano, CONH₂,CONHR⁹, CF₃, NH₂, NHCOR⁹ or NHCONHR⁹; R⁹ is a group R^(9a) or(CH₂)R^(9a), wherein R^(9a) is a monocyclic or bicyclic group which maybe carbocyclic or heterocyclic; the carbocyclic group or heterocyclicgroup R^(9a) being optionally substituted by one or more substituentsselected from halogen, hydroxy, trifluoromethyl, cyano, nitro, carboxy,amino, mono- or di-C₁₋₄ hydrocarbylamino; a group R^(a)—R^(b) whereinR^(a) is a bond, O, CO, X¹C(X²), C(X²)X¹, X¹C(X²)X¹, S, SO, SO₂, NR^(c),SO₂NR^(c) or NR^(c)SO₂; and R^(b) is selected from hydrogen,heterocyclic groups having from 3 to 12 ring members, and a C₁₋₈hydrocarbyl group optionally substituted by one or more substituentsselected from hydroxy, oxo, halogen, cyano, nitro, carboxy, amino, mono-or di-C₁₋₄ hydrocarbylamino, carbocyclic and heterocyclic groups havingfrom 3 to 12 ring members and wherein one or more carbon atoms of theC₁₋₈ hydrocarbyl group may optionally be replaced by O, S, SO, SO₂,NR^(c), X¹C(X²), C(X²)X¹ or X¹C(X²)X¹; R^(c) is selected from hydrogenand C₁₋₄ hydrocarbyl; and X¹ is O, S or NR^(c) and X² is ═O, ═S or═NR^(c); and wherein (I) the ancillary compound is selected from: (a)the group consisting of trastuzumab, cetuximab, erlotinib, gefitinib,bevacizumab, imatinib and sorafinib; (b) an ancillary PKB inhibitor; (c)a CDK inhibitor; (d) a COX-2 inhibitor; (e) a HDAC inhibitor; (f)temozolomide; (g) bortezimib; and (h) a combination of two or more of(a) to (g); or (II) the ancillary compound is a cytotoxic compoundselected from: (a) camptothecin compounds; (b) the group consisting of5-fluorouracil, fludarabine, gemcitabine, capecitabine, cytarabine,ralitrexed, pemetrexed and methotrexate; (c) vinca alkaloids; (d)taxanes; (e) epothilones; (f) platinum compounds; (g) the groupconsisting of an anthracycline derivative, mitoxantrone and apodophyllotoxin derivative; (h) the group consisting of nitrogen mustardcompound, a nitrosurea, cyclophosphamide, Busulfan and mitomycin C; and(i) a combination of two or more of (a) to (h); or (III) the ancillarycompound is selected from: (a) the group consisting of alemtuzumab,anti-CD20, CD22, CD33, or CD52, rituximab/rituxamab, tositumomab,gemtuzumab ozogamicin and bevacizumab; and (b) a combination of two ormore of (a); or (IV) the ancillary compound is selected from: (a) thegroup consisting of antiandrogens, antiestrogens, aromatase inhibitors,and GNRAs; (b) the group consisting of interferons and interleukins; (c)the group consisting of tretinoin, alitretinoin, and bexarotene; and (d)a combination of two or more of (a) to (c).
 2. A combination accordingto claim 1 comprising an ancillary compound and a compound of theformula (Ia):

or a salt, solvate, tautomer or N-oxide thereof; wherein R² and R³ areindependently selected from hydrogen, C₁₋₄ hydrocarbyl and C₁₋₄ acyl; orR² and R³ together with the nitrogen atom to which they are attachedform a saturated monocyclic heterocyclic group having 4-7 ring membersand optionally containing a second heteroatom ring member selected fromO and N; or one of R² and R³ together with the nitrogen atom to whichthey are attached and one or more atoms from the linker group A form asaturated monocyclic heterocyclic group having 4-7 ring members andoptionally containing a second heteroatom ring member selected from Oand N; or NR²R³ and the carbon atom of linker group A to which it isattached together form a cyano group; R⁴ is selected from hydrogen,halogen, C₁₋₅ saturated hydrocarbyl, cyano and CF₃; and R⁵ is selectedfrom hydrogen, halogen, C₁₋₅ saturated hydrocarbyl, cyano, CONH₂,CONHR⁹, CF₃, NH₂, NHCOR⁹ or NHCONHR⁹; and R⁹ is phenyl or benzyl eachoptionally substituted by one or more substituents selected fromhalogen, hydroxy, trifluoromethyl, cyano, nitro, carboxy, amino, mono-or di-C₁₋₄ hydrocarbylamino; a group R^(a)—R^(b) wherein R^(a) is abond, O, CO, X¹C(X²), C(X²)X¹, X¹C(X²)X¹, S, SO, SO₂, NR^(c), SO₂NR^(c)or NR^(c)SO₂; and R^(b) is selected from hydrogen, heterocyclic groupshaving from 3 to 12 ring members, and a C₁₋₈ hydrocarbyl groupoptionally substituted by one or more substituents selected fromhydroxy, oxo, halogen, cyano, nitro, carboxy, amino, mono- or di-C₁₋₄hydrocarbylamino, carbocyclic and heterocyclic groups having from 3 to12 ring members and wherein one or more carbon atoms of the C₁₋₈hydrocarbyl group may optionally be replaced by O, S, SO, SO₂, NR^(c),X¹C(X²), C(X²)X¹ or X¹C(X²)X¹.
 3. A combination according to claim 1wherein the portion R¹-A-NR²R³ is represented by the formulaR¹-(G)_(k)-(CH₂)_(m)—W—O_(b)—(CH₂)_(n)—(CR⁶R⁷)_(p)—NR²R³ wherein G isNH, NMe or O; W is attached to the group E and is selected from(CH₂)_(j)—CR²⁰, (CH₂)_(j)—N and (NH)_(j)—CH; b is 0 or 1, j is 0 or 1, kis 0 or l, m is 0 or 1, n is 0, 1, 2, or 3 and p is 0 or 1; the sum of band k is 0 or 1; the sum of j, k, m, n and p does not exceed 4; R⁶ andR⁷ are the same or different and are selected from methyl and ethyl, orCR⁶R⁷ forms a cyclopropyl group; and R²⁰ is selected from hydrogen,methyl, hydroxy and fluorine.
 4. A combination according to claim 3wherein k is 0, m is 0 or 1, n is 0, 1, 2 or 3 and p is
 0. 5. Acombination according to claim 1 wherein E is selected from1,4-phenylene, 1,3-phenylene, 2,5-pyridylene and 2,4-pyridylene, each ofwhich is unsubstituted or substituted by up to 4 substituents R⁸ asdefined in claim
 1. 6. A combination according to claim 1 wherein thecompound of formula (I) is a compound of the formula (II):

or a salt, solvate, tautomer or N-oxide thereof; wherein the group A isattached to the meta or para position of the benzene ring and q is 0-4.7. A combination according to claim 6 wherein the compound of formula(II) is a compound having the formula (III):

or a salt, solvate, tautomer or N-oxide thereof; where A′ is the residueof the group A.
 8. A combination according to claim 1 wherein thecompound of formula (I) is a compound having the formula (IV):

or a salt, solvate, tautomer or N-oxide thereof; wherein z is 0, 1 or 2,R²⁰ is selected from hydrogen, methyl, hydroxy and fluorine, providedthat when z is 0, R²⁰ is other than hydroxy.
 9. A combination accordingto claim 1 wherein the compound of formula (I) is a compound having theformula (V):

or a salt, solvate, tautomer or N-oxide thereof.
 10. A combinationaccording to claim 1 wherein R¹ is selected from phenyl, which isunsubstituted or bears one or more substituents selected from hydroxy;C₁₋₄ acyloxy; fluorine; chlorine; bromine; trifluoromethyl; cyano;CONH₂; nitro; C₁₋₄ hydrocarbyloxy and C₁₋₄ hydrocarbyl each optionallysubstituted by C₁₋₂ alkoxy, carboxy or hydroxy; C₁₋₄ acylamino;benzoylamino; pyrrolidinocarbonyl; piperidinocarbonyl;morpholinocarbonyl; piperazinocarbonyl; five and six membered heteroaryland heteroaryloxy groups containing one or two heteroatoms selected fromN, O and S; phenyl; phenyl-C₁₋₄ alkyl; phenyl-C₁₋₄ alkoxy;heteroaryl-C₁₋₄ alkyl; heteroaryl-C₁₋₄ alkoxy and phenoxy, wherein theheteroaryl, heteroaryloxy, phenyl, phenyl-C₁₋₄ alkyl, phenyl-C₁₋₄alkoxy, heteroaryl-C₁₋₄ alkyl, heteroaryl-C₁₋₄ alkoxy and phenoxy groupsare each optionally substituted with 1, 2 or 3 substituents selectedfrom C₁₋₂ acyloxy, fluorine, chlorine, bromine, trifluoromethyl, cyano,CONH₂, C₁₋₂ hydrocarbyloxy and C₁₋₂ hydrocarbyl each optionallysubstituted by methoxy or hydroxy.
 11. A combination according to claim10 wherein R¹ is a mono-chlorophenyl or dichlorophenyl group.
 12. Acombination according to claim 1 wherein R⁴ is selected from hydrogenand methyl and R⁵ is selected from hydrogen, methyl and cyano.
 13. Acombination according to claim 1 wherein R² and R³ are independentlyselected from hydrogen, C₁₋₄ hydrocarbyl and C₁₋₄ acyl.
 14. Acombination according to claim 13 wherein R² and R³ are independentlyselected from hydrogen and methyl.
 15. A combination according to claim14 wherein R² and R³ are both hydrogen.
 16. A combination according toclaim 1 wherein the compound of the formula (I) is selected from thegroup consisting of: 2-phenyl-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethylamine;3-phenyl-2-[3-(1H-pyrazol-4-yl)-phenyl]-propionitrile;2-[4-(3,5-dimethyl-1H-pyrazol-4-yl)-phenyl]-2-phenyl-ethylamine;2-(4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethylamine;2-[3-(3,5-dimethyl-1H-pyrazol-4-yl)-phenyl]-1-phenyl-ethylamine;3-phenyl-2-[3-(1H-pyrazol-4-yl)-phenyl]-propylamine;3-phenyl-2-[4-(1H-pyrazol-4-yl)-phenyl]-propylamine;{3-(4-chloro-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propyl}-methyl-amine;{3-(3,4-difluoro-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propyl}-methyl-amine;{3-(3-chloro-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propyl}-methyl-amine;3-(4-chloro-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propionamide;3-(4-chloro-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propylamine;3-(3,4-dichloro-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propylamine;4-(4-chloro-phenyl)-4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidine;4-(4-methoxy-phenyl)-4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidine;4-(4-chloro-phenyl)-1-methyl-4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidine;4-phenyl-4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidine;4-[4-(3,5-dimethyl-1H-pyrazol-4-yl)-phenyl]-4-phenyl-piperidine;dimethyl-{3-[4-(1H-pyrazol-4-yl)-phenyl]-3-pyridin-2-yl-propyl}-amine;{2-(4-chloro-phenyl)-2-[4-(1-pyrazol-4-yl)-phenyl]-ethyl}-dimethyl-amine;{2-(4-chloro-phenyl)-2-[4-(1-pyrazol-4-yl)-phenyl]-ethyl}-methyl-amine;{2-(4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-methyl-amine(R);{2-(4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-methyl-amine(S);4-{2-(4-chloro-phenyl)-2-[4-(1-pyrazol-4-yl)-phenyl]-ethyl}-morpholine;4-{4-[1-(4-chloro-phenyl)-2-pyrrolidin-1-yl-ethyl]-phenyl}-1H-pyrazole;{2-(4-chloro-phenyl)-2-[4-(1-pyrazol-4-yl)-phenyl]-ethyl}-isopropyl-amine;dimethyl-{2-phenyl-2-[4-(1-pyrazol-4-yl)-phenyl]-ethyl}-amine;{2,2-bis-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-dimethyl-amine;{2,2-bis-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-methyl-amine;2-(4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethylamine (R);2-(4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethylamine (S);2-(4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-acetamide;1-{2-(4-chloro-phenyl)-2-[4-(1-pyrazol-4-yl)-phenyl]-ethyl}-piperazine;1-{2-(4-chloro-phenyl)-2-[4-(1-pyrazol-4-yl)-phenyl]-ethyl}-piperidine;4-{4-[2-azetidin-1-yl-1-(4-chloro-phenyl)-ethyl]-phenyl}-1H-pyrazole;1-phenyl-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethylamine;2-(4-chloro-phenyl)-N-methyl-2-[4-(1H-pyrazol-4-yl)-phenyl]-acetamide;N-methyl-2,2-bis-[4-(1H-pyrazol-4-yl)-phenyl]-acetamide;{2-(4-chloro-phenyl)-2-[4-(1-pyrazol-4-yl)-phenyl]-ethyl}-methyl-amine;{2-(4-chloro-phenyl)-2-[4-(1-pyrazol-4-yl)-phenyl]-ethyl}-ethyl-amine;4-{4-[1-(4-chloro-phenyl)-2-imidazol-1-yl-ethyl]-phenyl}-1H-pyrazole;methyl-{2-(4-phenoxy-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-amine;{2-(4-methoxy-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-methyl-amine;methyl-{2-[4-(pyrazin-2-yloxy)-phenyl]-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-amine;methyl-{2-phenoxy-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-amine;2-{(4-chloro-phenyl)-[4-(1H-pyrazol-4-yl)-phenyl]-methoxy}-ethylamine;4-{4-[1-(4-chloro-phenyl)-3-pyrrolidin-1-yl-propyl]-phenyl}-1H-pyrazole;4-{4-[3-azetidin-1-yl-1-(4-chloro-phenyl)-propyl]-phenyl}-1H-pyrazole;methyl-{3-naphthalen-2-yl-3-[4-(1H-pyrazol-4-yl)-phenyl]-propyl}-amine;{3-(4-fluoro-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propyl}-methyl-amine;4-{4-[4-(4-chloro-phenyl)-piperidin-4-yl]-phenyl}-1H-pyrazole-3-carbonitrile;3-(4-phenoxy-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propylamine;1-{(4-chloro-phenyl)-[4-(1H-pyrazol-4-yl)-phenyl]-methyl}-piperazine;1-methyl-4-{phenyl-[4-(1H-pyrazol-4-yl)-phenyl]-methyl}-[1,4]diazepane;{3-(3-chloro-phenoxy)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propyl}-methyl-amine;methyl-{2-phenyl-2-[6-(1-pyrazol-4-yl)-pyridin-3-yl]-ethyl}-amine;4-{4-[1-(4-chloro-phenyl)-3-imidazol-1-yl-propyl]-phenyl}-1H-pyrazole;4-[4-(3-imidazol-1-yl-1-phenoxy-propyl)-phenyl]-1H-pyrazole;4-{4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidin-4-yl}-phenol;1-{(4-chloro-phenyl)-[4-(1H-pyrazol-4-yl)-phenyl]-methyl}-piperazine;{2-(4-fluoro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-methyl-amine;{2-(3-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-methyl-amine;4-[4-(2-methoxy-ethoxy)-phenyl]-4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidine;4-[4-(3-methoxy-propoxy)-phenyl]-4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidine;3-(3,4-dichloro-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propionamide;2-(4-{2-methylamino-1-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-phenoxy)-isonicotinamide;{2-(4-chloro-phenoxy)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-methyl-amine;3-{2-(4-chloro-phenyl)-2-[4-(1-pyrazol-4-yl)-phenyl]-ethylamino}-propan-1-ol;2-{2-(4-chloro-phenyl)-2-[4-(1-pyrazol-4-yl)-phenyl]-ethylamino}-ethanol;3-{2-(4-chloro-phenyl)-2-[4-(1-pyrazol-4-yl)-phenyl]-ethylamino}-propan-1-ol;{2-(4-chloro-phenyl)-2-[4-(1-pyrazol-4-yl)-phenyl]-ethyl}-cyclopropylmethyl-amine;methyl-[2-[4-(1H-pyrazol-4-yl)-phenyl]-2-(4-pyridin-3-yl-phenyl)-ethyl]-amine;4-{3-methylamino-1-[4-(1H-pyrazol-4-yl)-phenyl]-propyl}-phenol;3-(4-methoxy-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propylamine;4-(4-chloro-phenyl)-4-[4-(3-methyl-1H-pyrazol-4-yl)-phenyl]-piperidine;2-(4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-morpholine;(4-{4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidin-4-yl}-phenoxy)-acetic acid;4-{4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidin-4-yl}-benzonitrile;{2-(4-chloro-phenyl)-2-[4-(1-pyrazol-4-yl)-phenyl]-propyl}-methyl-amine;1-(4-chloro-phenyl)-2-methylamino-1-[4-(1H-pyrazol-4-yl)-phenyl]-ethanol;2-amino-1-(4-chloro-phenyl)-1-[4-(1H-pyrazol-4-yl)-phenyl]-ethanol;4-(3,4-dichloro-phenyl)-4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidine;4-(3-chloro-4-methoxy-phenyl)-4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidine;4-(4-chloro-3-fluoro-phenyl)-4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidine;4-[4-(1H-pyrazol-4-yl)-phenyl]-1,2,3,4,5,6-hexahydro-[4,4′]bipyridinyl;3-(3-chloro-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propylamine;2-methylamino-1-(4-nitro-phenyl)-1-[4-(1H-pyrazol-4-yl)-phenyl]-ethanol;2-(3-chloro-4-methoxy-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethylamine;2-(4-chloro-phenyl)-2-fluoro-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethylamine;3-(3,4-dichloro-phenyl)-3-[6-(1H-pyrazol-4-yl)-pyridin-3-yl]-propylamine;2-(4-chloro-3-fluoro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethylamine;4-(2-chloro-3-fluoro-phenyl)-4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidine;1-{(3,4-dichloro-phenyl)-[4-(1H-pyrazol-4-yl)-phenyl]-methyl}-piperazine;2-(3,4-dichloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethylamine;{2-(3-chloro-4-methoxy-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-methyl-amine;4-{4-[2-azetidin-1-yl-1-(4-chloro-phenoxy)-ethyl]-phenyl}-1H-pyrazole;3-(3-chloro-4-methoxy-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propylamine;{3-(3-chloro-4-methoxy-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propyl}-methyl-amine;1-{(3,4-dichloro-phenyl)-[4-(1H-pyrazol-4-yl)-phenyl]-methyl}-piperazine;and C-(4-chloro-phenyl)-C-[4-(1H-pyrazol-4-yl)-phenyl]-methylamine; andsalts, solvates, tautomers and N-oxides thereof.
 17. A combinationaccording to claim 1 in the form of a pharmaceutical pack, kit orpatient pack.
 18. A combination according to claim 1 wherein theancillary compound comprises: an antiandrogen, antiestrogen, aromataseinhibitor, or GNRA selected from tamoxifen, fulvestrant, raloxifene,toremifene, droloxifene, letrozole, anastrozole, exemestane,bicalutamide, luprolide, megestrol/megestrel acetate, vorozole,aminoglutethimide, bexarotene, goserelin, leuprolide/leuporelin,triptorelin, buserelin, abarelix, goserelin acetate and leuprolideacetate; an ancillary PKB inhibitor selected from SF1126, rapamycinanalogues, KRX-0401, API-2/TCN, RX-0201, enzastaurin HCl, SR-13668,PX-316, Perifosine, and NL-71-101; a CDK inhibitor selected fromseliciclib, alvocidib, 7-hydroxy-staurosporine, JNJ-7706621, BMS-387032,PHA533533, PD332991, ZK-304709, and AZD-5438; COX-2 inhibitor celecoxib;a HDAC inhibitor selected from TSA, SAHA, JNJ-16241199, LAQ-824,MGCD-0103, PXD-101, JNJ-16241199, LAQ-824, MGCD-0103, PXD-101,chlamydocin, and A-173; a camptothecin compound selected from irinotecanand topotecan; a vinca alkaloid selected from vinblastine, vincristine,vinorelbine, vindesine, and vinvesir; a taxane selected from paclitaxeland docetaxel; an epothilone selected from epothilone A, epothilone B,ixabepilone, patupilone, BMS-310705, BMS-247550, KOS-862 and ZK-EPO; ora platinum compound selected from chloro(diethylenediamino)-platinum(II) chloride, dichloro(ethylenediamino)-platinum (II), spiroplatin,iproplatin, diamino(2-ethylmalonato)platinum (II),(1,2-diaminocyclohexane)malonatoplatinum (II),(4-carboxyphthalo)-(1,2-diaminocyclohexane)platinum (II),(1,2-diaminocyclohexane)-(isocitrato)platinum (II),(1,2-diaminocyclohexane)-cis-(pyruvato)platinum (II), onnaplatin,tetraplatin, cisplatin, carboplatin and oxaliplatin.
 19. A combinationaccording to claim 1 containing two or more ancillary compounds.
 20. Acombination according to claim 19 wherein at least one of the twoancillary compounds and compound of formula (I), or a salt, solvate,tautomer or N-oxide thereof, are physically associated.
 21. Acombination according to claim 19 wherein at least one of the twoancillary compounds and compound of formula (I), or a salt, solvate,tautomer or N-oxide thereof, are non-physically associated.
 22. Acombination according to claim 1 wherein the compound of formula (I) is2-amino-1-(4-chloro-phenyl)-1-[4-(1H-pyrazol-4-yl)-phenyl]-ethanol, or asalt, solvate, tautomer or N-oxide thereof.
 23. A combination accordingto claim 22 wherein the compound of formula (I) is in the form of asalt.
 24. A combination according to claim 22 wherein the compound offormula (I) is in the form of a di-hydrochloride salt.
 25. A combinationaccording to claim 1 wherein the ancillary compound and compound offormula (I), or a salt, solvate, tautomer or N-oxide thereof, arephysically associated.
 26. A combination according to claim 1 whereinthe ancillary compound and compound of formula (I), or a salt, solvate,tautomer or N-oxide thereof, are non-physically associated.